Propranolol in Treating Hypoglycemia Unawareness

Impaired awareness of hypoglycemia is common in type 1 diabetes (T1DM) patients. Impaired hypoglycemia awareness increases severe hypoglycemia risk by six-fold. Severe hypoglycemia compromises quality of life and can potentially cause death. The long-term goal of this pilot study is to lead to the development of novel therapeutic approaches to improve hypoglycemia awareness and thus prevent severe hypoglycemia development in T1DM population with impaired awareness of hypoglycemia. It is hypothesized that propranolol will improve hypoglycemia recognition in T1DM. The specific aims of the study are to determine whether propranolol treatment improves subjects' recognition of hypoglycemic episodes, and improves hypoglycemic awareness scores; whether propranolol favorably increases hypoglycemia blood glucose nadir, decreases onset-to-treatment/recovery time (i.e. hypoglycemia duration), and reduces hypoglycemia/severe hypoglycemia frequency; and, whether propranolol reduces fear of hypoglycemia and improves overall blood glucose control.

Type 1 diabetes mellitus (T1DM) can lead to serious and devastating complications, including microvascular (retinopathy, neuropathy and nephropathy) and cardiovascular disease. Both diabetic microvascular and cardiovascular complications can be reduced with intensive insulin therapy and strict blood glucose control which target hemoglobin A1C to less than 7%. However, tighter glycemic control correlates with a higher incidence of hypoglycemia and severe hypoglycemia. Recurring exposure to hypoglycemia leads to an attenuated sympathoadrenal response to hypoglycemia (which is termed hypoglycemia-associated autonomic failure), and thus a loss or decrease in neurogenic hypoglycemic symptoms (i.e. impaired awareness of hypoglycemia). Impaired awareness of hypoglycemia is associated with a six-fold increased risk of severe hypoglycemia and physician or patient-directed higher glycemic goals. Impaired awareness of hypoglycemia is therefore a major barrier in diabetes management, by precluding optimal glycemic control and realization of its full benefits. Several therapeutic strategies have been proposed to improve hypoglycemia awareness in T1DM patients. A temporal increase in glycemic goal only sustains hypoglycemia awareness recovery for a short-term. Islet transplantation is invasive, extremely expensive and requires life-long use of immunosuppressants. A widely available and affordable treatment with sustained efficacy for improving hypoglycemia awareness is therefore in urgent need. Pharmaceutical agents targeting potential mechanisms that contribute to the development of impaired hypoglycemia awareness have been proposed, including beta-blockers, opioid receptor antagonists and selective serotonin uptake inhibitors (SSRIs). However, none of these agents has been approved for the treatment of impaired hypoglycemia awareness. The current pilot study will examine the clinical use of beta-blockers, specifically propranolol, for the treatment of impaired hypoglycemia awareness. In a physiological condition, hypoglycemia leads to counterregulatory hormone responses, including catecholamines. Catecholamine elevation mediates the development of neurogenic symptoms, including palpitation, anxiety and diaphoresis, and patient's recognition of a hypoglycemic episode. Previous study suggests that recurring hypoglycemic events, potentially through repeated ventromedial hypothalamus (VMH) noradrenergic system activation, dampen the counterregulatory hormone response to hypoglycemia. In addition, carvedilol (a non-specific beta-blocker) prevented hypoglycemia-associated autonomic failure development in rats made recurrently hypoglycemic. Consistent with these findings, propranolol, which crosses blood brain barrier and blocks beta-2 adrenergic receptors, has been shown to prevent hypoglycemia-associated autonomic failure in healthy human subjects. Thus, an intervention which can block the propagating mechanism(s) (i.e. repeated activation of beta2-adrenergic receptors) will likely lead to sympathoadrenal function improvement, and thus increase hypoglycemic symptoms and hypoglycemia awareness. Beta-blocker is one of the most extensively used medication classes in the United States, and has been commonly utilized in diabetes patients for cardiac diseases. Although beta-blocker may theoretically attenuate hypoglycemic symptoms or lead to worsening of hypoglycemia, multiple studies have proven that beta-blockers increase hypoglycemic symptoms and can be safely used in insulin-dependent diabetes patients. In particular, a retrospective study included more than 13,000 patients and examined the relationship between antihypertensive use and hypoglycemia, and this study supported that beta-blocker use was not associated with an increase in severe hypoglycemia. As well, in a recent post-hoc analysis of a large type 2 diabetes intensive insulin therapy study (ACCORD), the group receiving beta-blocker and intensive insulin therapy had fewer cardiovascular events and comparable all-cause and cardiovascular death events compared to the group receiving beta-blocker and conventional therapy; this is thus evident for the safety of beta-blocker usage in patients undergoing intensive insulin therapy. With the safety data and previous basic/clinical observations, it is therefore proposed that propranolol is a strong testing candidate for potential hypoglycemia-associated autonomic failure treatment.

After enrollment and the initial two-week continuous glucose monitoring assessment, study subjects randomized to the Propranolol Arm will be treated with Propranolol 80 Mg Oral Capsule, Extended Release daily for four weeks.

After enrollment and the initial two-week continuous glucose monitoring assessment, study subjects randomized to the Placebo Arm will be treated with matching placebo oral capsule daily for four weeks.

Ratio of Self-reported Hypoglycemic Episodes to Total Hypoglycemic Episodes Determined by Continuous Glucose Monitoring (CGM)

A subject's self-reported hypoglycemic episode is defined by a hypoglycemic symptom record on the hypoglycemia diary with a confirmatory glucose value (glucometer value < 70 mg/dL), or an incidental glucometer value < 70 mg/dL if no hypoglycemia symptom develops. A single CGM hypoglycemic episode is defined by any CGM readings < 70 mg/dL, followed by at least one reading ≥ 70 mg/dL from the Dexcom Professional Mobile CGM system. Self-reported and CGM assessment of hypoglycemic episodes will be conducted for two weeks before study drug intervention and two weeks after study drug intervention. The average change in the ratio of self-reported hypoglycemic episodes to total (CGM) episodes will be compared between the propranolol and placebo treatment arms

Subjects will complete the Gold questionnaire for hypoglycemia awareness at the baseline and at the last visit of the intervention period. The Gold questionnaire is comprised of one question to evaluate the hypoglycemia awareness, with scores from 1 to 7, representing from normal to minimal/no hypoglycemia awareness. The average change in Gold questionnaire score from baseline to the last visit will be compared between the propranolol and placebo treatment arms.

Subjects will complete the Clarke questionnaire for hypoglycemia awareness at the baseline and at the last visit of the intervention period. The Clarke questionnaire is comprised of eight questions to evaluate the hypoglycemia awareness. The answer for each individual question will represent a score (0 or 1). These scores will be summed together to a final score from 0 to 7, representing from normal to minimal/no hypoglycemia awareness. The average change in Clarke questionnaire score from baseline to the last visit will be compared between the propranolol and placebo treatment arms.

Subjects will complete the Pederson-Bjergaard questionnaire for hypoglycemia awareness at the baseline and at the last visit of the intervention period. The Pederson-Bjergaard questionnaire is comprised of one question to evaluate the hypoglycemia awareness, with answers of "Always", "sometimes", "occasionally", "never" or "Do not know". Each answer will represent an awareness status. The change in Pederson-Bjergaard questionnaire status from baseline to the last visit will be compared between the propranolol and placebo treatment arms.

Nadir glucose level during each hypoglycemic episode will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The average of nadir blood glucose levels will be calculated and the change will be compared between the propranolol and placebo treatment arms.

Nadir glucose level during each hypoglycemic episode will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The number of hypoglycemic events will be totaled in the severity categories of nadir glucose level: < 70 mg/dL; < 60 mg/dL; < 56 mg/dL; < 50 mg/dL; and < 40 mg/dL. The change in the number of hypoglycemic events in these categories will be compared between the propranolol and placebo treatment arms.

Duration of hypoglycemia will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The total duration of hypoglycemia (in minutes) will be calculated for each duration categories of hypoglycemia: <15 minutes, ≥ 15 minutes, ≥ 30 minutes, ≥ 45 minutes and ≥ 60 minutes. The change in the total time of hypoglycemia in these categories will be compared between the propranolol and placebo treatment arms.

Blood glucose will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The AUC of blood glucose will be calculated for each severity categories of nadir glucose level: < 70 mg/dL; < 60 mg/dL; < 56 mg/dL; < 50 mg/dL; and < 40 mg/dL. The change in AUC of these categories will be compared between the propranolol and placebo treatment arms.

The time of hypoglycemic symptom and glucometer reading of each hypoglycemic episode will be documented by study subjects in the hypoglycemia diary, and the onset time of hypoglycemia will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The duration of hypoglycemia onset-to-diagnosis will be calculated as the time difference between hypoglycemia onset as recorded on CGM, and documented hypoglycemic symptom and glucometer reading, whichever is the earliest. The change in the average duration of hypoglycemia onset-to-diagnosis will be compared between the propranolol and placebo treatment arms.

The time of hypoglycemia treatment of each hypoglycemic episode will be documented by study subjects in the hypoglycemia diary, and the onset time of hypoglycemia will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The duration of hypoglycemia onset-to-treatment will be calculated as the time difference between hypoglycemia onset as recorded on CGM, and documented hypoglycemia treatment. The change in the average duration of hypoglycemia onset-to-treatment will be compared between the propranolol and placebo treatment arms.

The time of hypoglycemic symptom and glucometer reading of each hypoglycemic episode will be documented by study subjects in the hypoglycemia diary, and the recovery time of hypoglycemia will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The duration of hypoglycemia diagnosis-to-recovery will be calculated as the time difference between the documented hypoglycemic symptom and glucometer reading, whichever is the earliest, and hypoglycemia recovery as recorded on CGM. The change in the average duration of hypoglycemia diagnosis-to-recovery will be compared between the propranolol and placebo treatment arms.

The time of hypoglycemia treatment of each hypoglycemic episode will be documented by study subjects in the hypoglycemia diary, and the recovery time of hypoglycemia will be detected by CGM during a 2-week interval at baseline and at the end of the treatment period. The duration of hypoglycemia treatment-to-recovery will be calculated as the time difference between the documented hypoglycemia treatment and hypoglycemia recovery as recorded on CGM. The change in the average duration of hypoglycemia treatment-to-recovery will be compared between the propranolol and placebo treatment arms.

Hypoglycemia will be reported by patients detected by CGM during a 2-week interval at the baseline and at end of the treatment period. The total number of hypoglycemic episodes as defined by CGM readings of < 70 mg/dL will be counted, and the changes in the number will be compared between the propranolol and placebo treatment arms.

Severe hypoglycemia is a clinical event defined by any hypoglycemic episode requiring outside help in the treatment administration of the particular hypoglycemic episode. Severe hypoglycemia episodes will be recorded by hypoglycemia diary during a 2-week interval at baseline and at the end of the treatment period. The total number of hypoglycemia/severe hypoglycemia episodes as defined by CGM readings of < 70 mg/dL will be counted and the change will be compared between the propranolol and placebo treatment arms.

Subjects will complete the Fear of Hypoglycemia Questionnaire at baseline and the last visit of the intervention period. The average change in Fear of Hypoglycemia Questionnaire score from baseline to 4 weeks will be compared between the propranolol and placebo treatment arms.

Blood glucose will be detected by CGM during a 2-week interval at the baseline and at the end of the treatment period. The average change will be compared between the propranolol and placebo treatment arms.

Inclusion Criteria: Subjects with Type 1 diabetes mellitus for more than 5 years with impaired awareness of hypoglycemia Age between 21 to 59 years old Hemoglobin A1c ≤ 9%; most recent value within 3 months No beta-blocker use history in the last 6 months Able to provide informed consent and willing to sign an approved consent form that conforms to federal and institutional guidelines Exclusion Criteria: History of coronary, cerebral or peripheral vascular disease History of cardiac conduction abnormality or heart failure History of advanced liver disease Active malignancy Major Central or Peripheral Nervous System disease History of human immunodeficiency virus infection Contraindication to beta-blockers, including hypersensitivity to beta-blocker and bronchospastic disease Female in pregnancy or not able to practice effective contraception during the study period Concomitant acetaminophen use Currently utilizing unblinded real-time continuous glucose monitoring Advanced diabetic microvascular complications including retinopathy, neuropathy and nephropathy Inability to understand or cooperate with study procedure, including performing glucometer glucose assessment a minimum of four times a day, carrying glucose tablets and following standardized hypoglycemia treatment, completing hypoglycemia diary, wearing continuous glucose monitoring, and using a single glucometer Recent or current use or involvement in clinical studies of other therapies (e.g. opioid antagonist, SSRI, behavioral modification, relaxation of glycemic control) that may improve hypoglycemia awareness or prevent impaired hypoglycemia awareness development

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