Project Summary/Abstract
Intensive insulin treatment decreases the risk of micro- and macrovascular complications in type 1 diabetes
(T1D) but is associated with a higher risk of severe hypoglycemia, limiting optimal glycemic control. Over time,
20-30% of patients with T1D develop impaired awareness of hypoglycemia (IAH), most likely as a
consequence of repeated and severe episodes of hypoglycemia. IAH is, itself, a significant risk factor for
subsequent episodes of severe hypoglycemia, leading to a vicious cycle with potentially lethal consequences.
IAH is associated with diminished counter-regulatory responses (CRR) to hypoglycemia and changes in brain
structure and function. Reducing the frequency of hypoglycemia with advanced technologies (continuous
glucose monitoring [CGM] and insulin pumps) and targeted education improves IAH, but not completely.
The Advanced Insulin Delivery to Reduce Impaired Awareness of Hypoglycemia in a Type 1 Diabetes Cohort
(AIDRIAHT1C) trial aims at testing the efficacy of HCL compared to sensor-augmented pump (SAP) therapy to
improve awareness of hypoglycemia and CRR by reducing the amount of time spent in hypoglycemia. The
study will enroll a diverse population of adults with T1D of at least ten years duration. Participants will be
classified as having IAH using the HYPO score. Individuals with IAH will be randomized 1:1 to the two
interventions and both groups will receive a targeted educational program designed to decrease hypoglycemia.
At baseline and at 6-month intervals for 2 years, participants will undergo step-wise hyperinsulinemic-
hypoglycemic clamps. The primary outcome, assessed at 12 months, consists of the co-primary endpoints of
CRR to hypoglycemia (endogenous glucose production, pancreatic polypeptide, and epinephrine, tested
hierarchically) and symptom recognition (autonomic symptom score, HYPO score, also tested hierarchically)
(Aim 1). Factors associated with IAH and the restoration of hypoglycemia awareness will be determined from
the screened population and the participants in the trial (Aim 2). A matched control group of healthy non-
diabetic controls and of participants with T1D and normal awareness of hypoglycemia will be enrolled to
provide normative responses to hypoglycemia at baseline. The study also aims at developing new approaches
to diagnosing IAH by testing combinations of self-reported items, CGM-prompted reporting, and physiological
monitoring, and predicting responses to intervention using machine learning and artificial intelligence (Aim 3)
and at studying brain structure and function associated with and predictive of IAH improvement (Aim 4) using
fMRI, with and without hypoglycemia.
The ultimate goals of the study are to identify the best treatment for IAH, develop better ways to identify
individuals at risk, understand the mechanisms of IAH and, ultimately, to reduce the burden and risks associated
with severe hypoglycemia and improve quality of life and treatment satisfaction in patients with T1D.
