Propranolol in Treating Hypoglycemia Unawareness
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.
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