This column highlights clinical trial data and landmark trials. Information for obtaining trial data and the references to the published articles are provided to facilitate discussion with your patients/colleagues. The trial is identified by the acronym and the National Clinical Trials Identifier. Primary outcome results are summarized.
Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: A multicenter, 12-week randomized trial
Study title acronym: APCam11
ClinicalTrials.gov identifier: NCT02523131
Reference: 1. Tauschmann M, Thabit H, Bally L, Allen JM, Hartnell S, Wilinska ME, et al. Closed-loop insulin delivery in suboptimally controlled type 1 diabetes: A multicentre, 12-week randomised trial. Lancet. 2018;392(10155):1321-1329.
Sponsor: JDRF, National Institute for Health Research (NIHR) and Wellcome Trust
Study design: A phase 2/3, multicenter, multinational (U.K., four sites, and U.S., two sites), open-label, randomized, parallel design trial in which 86 individuals ≥ 6 years of age with Type 1 diabetes (T1D duration ≥ 1 year) and suboptimal metabolic control on insulin-pump therapy (HbA1c of 7.5-10 percent and not routinely using continuous glucose monitoring [CGM]) were randomly assigned to either hybrid closed-loop insulin delivery (i.e., “artificial pancreas;” n=46) or sensor-augmented (real-time CGM) pump therapy (i.e., “control;” n=40) for a 12-week period of unsupervised routine living. The objective was to compare the therapeutic efficacy, safety and psychosocial effect of a 24-hour, hybrid closed-loop insulin delivery system with sensor-augmented insulin pump therapy, when used for longer duration and across a more age-diverse population (children, adolescents and adults) than in previous comparative trials. Pregnancy or planned pregnancy, untreated celiac disease, adrenal insufficiency or hypothyroidism, significant diabetic co-morbidity or use of other glucose-altering medications were exclusion criteria. Participants in both groups were trained in the use of a modified 640G investigational insulin pump (Medtronic; Northridge California) and the Enlite 3 real-time glucose sensor (Medtronic). For participants randomized to the closed-loop arm, a treat-to-target control algorithm was employed to adjust the insulin infusion rate to achieve glucose readings between 104-131 mg/dL (U.K. sites: 5.8–7.3 mmol/L). In this way, a comparison of algorithmically driven vs. non-algorithmic insulin delivery could be examined.
Primary outcome: The between-group difference in the percentage of time spent in target glucose range (70–180 mg/dL or 3.9–10.0 mmol/L) at 12 weeks, determined by sensor-measured glucose concentrations.
Other outcomes: Secondary outcomes included HbA1c value at 12 weeks; mean sensor glucose over 12 weeks; percentage of time in hypoglycemia (<70 mg/dL) or hyperglycemia (>180 mg/dL); area-under-curve for glucose <63 mg/dL; frequency of severe hypoglycemic episodes or significant ketosis; daily insulin requirements; change in body weight; and impact on quality of life, as determined by the Pediatric Quality of Life Inventory (PedsQL) questionnaire.
Results: After 12 weeks of intervention, participants in the closed-loop insulin delivery group experienced: 1) longer blood glucose time-in-range (+10.8 percent, p<0.0001); 2) lower HbA1c (7.4 percent vs. 7.7 percent, p<0.0001); and 3) shorter time spent in a hypoglycemic (-0.83 percent, p<0.0013) or hyperglycemic (-10.3 percent, p<0.0001) range compared with the control group. Additionally, these improvements occurred in subjects of all ages; these improvements were also achieved without any comparative increase in daily insulin dose, body weight gain or psychosocial burden. The safety profile was acceptable and similar for both therapies; however, more unscheduled study contacts were required for participants in the closed-loop group due to periodic technical issues.
Summary: The authors describe their study as providing the largest and longest duration comparative study of “artificial pancreas” system use during routine free-living conditions available to date. As such, the results demonstrated that in a “real-world” setting, hybrid closed-loop therapy safely provided a significant improvement in glucose control, particularly overnight, along with reduction in hypoglycemic risk, across a wide age range of participants, providing confirmation of the benefits of artificial pancreas therapy for T1D within the subgroup of patients studied. Longer-term data will be needed to establish broader conclusions about artificial pancreas use, particularly as related to feasibility and econometric assessments.
Predictive low-glucose suspend reduces hypoglycemia in adults, adolescents, and children with type 1 diabetes in an at-home randomized crossover study: Results of the PROLOG trial
Study title acronym: PROLOG [Predictive low-glucose suspend (PLGS) for Reduction Of LOw Glucose]
ClinicalTrials.gov identifier: NCT03195140
Reference: 1. Forlenza GP, Li Z, Buckingham BA, Pinsker JE, Cengiz E, Wadwa RP, et al. Predictive low-glucose suspend reduces hypoglycemia in adults, adolescents, and children with type 1 diabetes in an at-home randomized crossover study: Results of the PROLOG trial. Diabetes care. 2018;41(10):2155-61.
Sponsor: Tandem Diabetes Care
Study design: A multicenter (U.S., 4 sites), open-label, randomized controlled 6-week crossover trial of 103 individuals ≥ 6 years of age with type 1 diabetes (T1D duration ≥ 1 year) randomly assigned to two 3-week intervention periods, one utilizing insulin pump therapy with a predictive low-glucose suspend (PLGS) algorithm, and the other utilizing standard, sensor-augmented pump therapy without PLGS. The insulin pump PLGS system for the trial was the Tandem Diabetes Care insulin pump with integrated Dexcom G5 sensor, referred to as the “t:slim X2 with Basal-IQ technology.” This PLGS algorithm predicts glucose trends 30 minutes into the future and suspends insulin delivery for any predicted glucose <80 mg/dL or actual glucose <70 mg/dL, as determined by serial sensor-measured glucose concentrations. With a crossover design, each individual served as their own control for the study. Uncontrolled thyroid disease; renal failure; a major bleeding disorder; or unstable cardiovascular diseases were among the exclusion criteria. However, there were no specifications regarding pre-trial mode of insulin therapy (injections or pump), pre-trial continuous glucose monitor (CGM) use, or baseline HbA1c measurement for enrollment. Pump and CGM training was, therefore, individualized to each subject, based upon the participants prior device experience.
Primary outcome: CGM-measured percentage of time spent with glucose <70 mg/dL in each 3-week period.
Other outcomes: Secondary outcomes included percentage of glucose values <60 mg/dL; percentage of glucose values <50 mg/dL; Area-under-curve (AUC) for glucose <70 mg/dL; frequency of CGM-measured hypoglycemic events; percentage of time in target glucose range (70 to 180 mg/dL); percentage of time in hyperglycemic range (>180 mg/dL or >250 mg/dL); incidence of ketosis; daily insulin requirements; and participant satisfaction with the PLGS system.
Results: All outcomes favored the PLGS treatment arm. During the 3-week period using PLGS technology, patients experienced a significant reduction in time spent with glucose <70 mg/dL (i.e., primary outcome was achieved; p<0.001), <60 mg/dL (p<0.001), <50 mg/dL (p<0.002) and frequency of CGM-defined hypoglycemia events (p<0.001), with the greatest benefit coming to those with the most hypoglycemia exposure at baseline. Interestingly, participant average glucose levels did not differ during the two treatment periods and there was no observed compensatory increase in hyperglycemia during the PLGS treatment period, perhaps attributable to the fact that the mean duration of insulin suspension was only 18 minutes per event. Mean basal insulin delivery was slightly lower during the PLGS period (1.2 units/day or ~4% reduction) while bolus insulin delivery was no different between the treatment groups. Additionally, there were no significant safety concerns for severe hypoglycemia or diabetic ketoacidosis during the PLGS period. Overall, use of the PLGS algorithm resulted in a significant reduction in hypoglycemia and was given high scores for system usability.
Summary: Short-term (3-week) use of the Tandem Diabetes Care Basal-IQ PLGS system, compared with use of standard sensor-augmented pump therapy, decreased hypoglycemia without rebound hyperglycemia, in patients of all ages with T1D. Moreover, the short duration of insulin suspension produced by the PLGS algorithm may not effectively remedy more prolonged hypoglycemic events. Consequently, longer-term studies will be needed to assess the impact of this pump technology on metabolic control, safety and feasibility, not yet established by this study.
Effects of aspirin for primary prevention in persons with diabetes mellitus
Study title acronym: ASCEND
ClinicalTrials.gov identifier: NCT00135226
References: 1. Bowman L, Mafham M, Wallendszus K, Stevens W, Buck G, Barton J, et al.; ASCEND Study Collaborative Group. Effects of aspirin for primary prevention in persons with diabetes mellitus. New England Journal of Medicine. 2018;379(16):1529-1539.
2. American Diabetes Association. Standards of Medical Care in Diabetes-2019. 10. Cardiovascular disease and risk management. Diabetes Care. 2019;42(suppl 1):S103-S123.
Sponsors: University of Oxford, British Heart Foundation, Bayer, EPD Research Limited, Medical Research Council
Study design: Randomized, placebo-controlled trial in adults with diabetes mellitus and no history of cardiovascular events were assigned to aspirin 100 mg daily or placebo.
Primary outcome: First serious vascular event (myocardial infarction, stroke, transient ischemic attack or death from any vascular cause, except of intracranial hemorrhage). Primary safety outcomes were first major bleeding event (intracranial hemorrhage, sight-threatening bleeding in the eye, gastrointestinal bleeding or other serious bleeding).
Results: Patients (N=15,480) underwent randomization to aspirin or placebo. After follow-up of 7.4 years, serious vascular events were 8.5 percent in the aspirin group compared to 9.6 percent in placebo group (P=0.01). Major bleeding events occurred in 4.1 percent of patients in the aspirin group compared to 3.2 percent in the placebo group (P=0.003). Most of the serious bleeding events were gastrointestinal bleeding.
Summary: The use of aspirin for primary prevention of cardiovascular disease in patients with diabetes remains controversial. This study demonstrates aspirin does have efficacy in primary prevention of cardiovascular events in patients with diabetes mellitus. An increased risk of bleeding with aspirin was shown, which at least partially negates the beneficial effects of aspirin. The American Diabetes Association 2019 Standards of Medical Care in Diabetes recommends that aspirin be considered for primary prevention in patients with diabetes who are at increased risk of cardiovascular disease and are not at increased risk of bleeding. Clinicians must counsel patients on the risks and benefits of aspirin before recommending that patients take this commonly used medication.
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About our experts: Kathryn Thrailkill, MD, Professor of Pediatrics, Division of Pediatric Endocrinology, Barnstable Brown Endowed Chair in Pediatric Diabetes Research, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky
Derick Adams, DO, Assistant professor, internal medicine, Division of Endocrinology, Endocrinology Fellowship associate program director, Barnstable Brown Diabetes Center, University of Kentucky, Lexington, Kentucky