Propranolol in Treating Hypoglycemia Unawareness

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