The purpose of this FOA is to establish a clinical consortium to determine the factors that contribute to the heterogeneity in the restoration of impaired awareness of hypoglycemia (IAH) and improved counter-regulatory responses in adult individuals with Type 1 Diabetes (T1D). Individuals with IAH are often excluded from clinical trials and this omission contributes greatly to a lack of knowledge regarding the clinical characteristics which determine or predict an individual’s ability to restore hypoglycemic awareness. New technologies such as continuous glucose monitors (CGM) and closed loop systems (i.e. artificial pancreas) have been shown to reduce hypoglycemic events. However, despite a reduction in hypoglycemic events, restoration of hypoglycemia awareness does not occur in all individuals and the effects on improving the counter-regulatory responses are not known.
The goals of the clinical consortium will be to 1) determine if the most up-to-date management strategies using diabetes technology to optimize HbA1c while minimizing hypoglycemia can restore awareness of hypoglycemia and improve counter-regulatory responses in individuals with T1D and IAH; 2) identify the magnitude and duration of time in range (TIR), time spent in hypoglycemia or other CGM metrics that are associated with restoration of awareness of hypoglycemia; and 3) determine the association of current or newly developed self-reported measures of IAH with counter-regulatory responses to elucidate the heterogeneity in restoration of hypoglycemia awareness. It is expected that state of the art metabolic assessments such as hypoglycemic, hyperinsulinemic clamps for the measurement of counter-regulatory responses will be utilized to determine restoration of awareness and validate self-report assessments.
Hypoglycemia remains a major limiting factor in the optimal treatment of Type 1 Diabetes (T1D). The glycemic goal of HbA1c <6.5%, as recommended by guidelines, and shown to minimize diabetic complications is associated with an increased incidence of severe hypoglycemia, defined as severe cognitive impairment requiring assistance for recovery. Repeated episodes of hypoglycemia result in impaired awareness of hypoglycemia (IAH) which contributes to diminished CNS-mediated recognition of the need for external glucose and the blunting of counter-regulatory responses (CRR) such as increased endogenous glucose production, glucagon release and sympathoadrenal responses required to increase blood glucose. This induces a vicious feed-forward cycle resulting in increased risk of hypoglycemic episodes, morbidity and mortality.
New technologies including continuous glucose monitors (CGM) and artificial pancreas devices alert patients to declining levels of glucose and have raised hopes as to their ability to reduce hypoglycemic events and restore awareness. However, evidence is emerging that even with CGM usage and a reduction in hypoglycemic events, a large proportion of individuals can still be classified as having IAH based on self-reported measures such as the Gold or Clarke scales. In fact, depending on the study, it has been shown that 30—80% of individuals on CGM have persistent IAH. Compounding the problem is that many individuals with T1D are not able or willing to take advantage of these technologies or may not use the CGM consistently.
Individuals with T1D and IAH are often excluded from clinical studies. In the few studies that have specifically recruited individuals with T1D and IAH, educational and behavioral interventions were effective in reducing hypoglycemic events and IAH in some but not all individuals. With the recognition that severe hypoglycemia is more common in T1D individuals with IAH compared with those without IAH and is associated with increased morbidity and mortality, understanding the physiological factors that contribute to restoration of impaired awareness will be critical to developing mitigation strategies whose goal is to improve treatment as well as determining optimal glycemic targets on an individual level.
The prevalence of IAH is higher in older T1D individuals and those with longer disease duration and appears significantly lower in individuals with disease duration less than 10 years. Thus, age and duration of diabetes appear to be risk factors for the development of IAH, but we do not know if these factors contribute to the heterogeneity in an individual’s ability to restore awareness of hypoglycemia. Contributing to the lack of clarity, we still do not know the minimal time spent in target range (time in range, TIR) or time spent in the hypoglycemic range that is necessary for amelioration of IAH and restoration of defective CRR.
Identification of the presence or absence of impaired awareness of hypoglycemia within individuals for classification into clinical trials is typically based on scores of > 4 in self-reported measures such as the Gold or Clarke questionnaires. Both questionnaires were originally validated in the 1990s before the common use of CGMs and the development of the artificial pancreas. While existing questionnaires may adequately identify IAH, there are limitations associated with each and neither questionnaire was designed to tease out the heterogeneity of an individual’s ability to restore awareness and relate this to physiological responses during hypoglycemia. None of the current questionnaires address the important clinical issue of nocturnal hypoglycemia. New patient reported outcome measures such as the HypoA-Q are promising but cut-off points for the presence or absence of IAH have yet to be identified. Therefore, composite metrics of existing questionnaires or new reliable and meaningful self-report questionnaires may need to be developed. Reliable self-reported measures of hypoglycemia awareness that could identify an individual’s ability to restore awareness and associated counter-regulatory responses would facilitate conduct of future clinical trials.
Thus, in light of all the changes in diabetes care over the past thirty years, it is incumbent to re-examine the relationship between the self-reported measures of IAH and the associated individual counter-regulatory responses including for example, endogenous glucose production, in a larger group of individuals with T1D to determine if the physiological measures truly reflect the clinical symptoms of impaired awareness of hypoglycemia.
In summary, the inclusion of individuals with T1D and IAH in clinical trials has been limited and the few studies conducted are small in size. This has hampered our understanding of the factors which contribute to the restoration of hypoglycemia unawareness and improved counter-regulatory responses. The objectives of the clinical consortium established by this FOA will be to design a study which will: 1) determine if hypoglycemia awareness can be restored in individuals with IAH and T1D using up-to-date management of diabetes; 2) identify the CGM metrics associated with restoration of awareness of hypoglycemia; and 3) determine the association of self-reported measures of IAH with counter-regulatory responses to elucidate the heterogeneity in restoration of hypoglycemia awareness. Findings from this clinical trial are expected to make a significant contribution to our understanding of the physiological factors which contribute to restoration of impaired awareness of hypoglycemia and be used to tailor treatment regimens for adult individuals with T1D and IAH.
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