Clinical trial NCT03161964: Propranolol in Treating Hypoglycemia Unawareness
Official title: Propranolol as a Treatment for Impaired Awareness of Hypoglycemia in Type 1 Diabetes
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
Conditions: Type 1 Diabetes Mellitus
Keywords: Hypoglycemia
Impaired Awareness of Hypoglycemia
Propranolol
Lead sponsor: University of Utah
Sponsor class: OTHER
First posted: 2017-05-22
Enrollment: 2
Sex: ALL
Minimum age (years): 21
Maximum age (years): 59
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Ratio of Self-reported Hypoglycemic Episodes to Total Hypoglycemic Episodes Determined by Continuous Glucose Monitoring (CGM)
timeFrame: 2 weeks
Secondary outcomes:
measure: Gold Questionnaire Score for Hypoglycemia Awareness
timeFrame: 4 weeks
measure: Clarke Questionnaire Score for Hypoglycemia Awareness
timeFrame: 4 weeks
measure: Pederson-Bjergaard Questionnaire Score for Hypoglycemia Awareness
timeFrame: 4 weeks
measure: Nadir Glucose Level
timeFrame: 2 weeks
measure: Nadir Glucose Level in Categories
timeFrame: 2 weeks
measure: Hypoglycemia Duration
timeFrame: 2 weeks
measure: Blood Glucose Area Under the Curve (AUC)
timeFrame: 2 weeks
measure: Duration of Hypoglycemia Onset-to-Diagnosis
timeFrame: 2 weeks
measure: Duration of Hypoglycemia Onset-to-Treatment
timeFrame: 2 weeks
measure: Duration of Hypoglycemia Diagnosis-to-Recovery
timeFrame: 2 weeks
measure: Duration of Hypoglycemia Treatment-to-Recovery
timeFrame: 2 weeks
measure: Total Hypoglycemia Episodes
timeFrame: 2 weeks
measure: Total Severe Hypoglycemia Episodes
timeFrame: 2 week
measure: Fear of Hypoglycemia Score
timeFrame: 4 weeks
measure: Mean Blood Glucose
timeFrame: 2 weeks
Other outcomes:
Locations:
city: Salt Lake City
country: United States
facility: University of Utah
state: Utah
Study officials:
affiliation: University of Utah
name: Anu Sharma, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Diabetes Control and Complications Trial Research Group; Nathan DM, Genuth S, Lachin J, Cleary P, Crofford O, Davis M, Rand L, Siebert C. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993 Sep 30;329(14):977-86. doi: 10.1056/NEJM199309303291401.
citation: Hypoglycemia in the Diabetes Control and Complications Trial. The Diabetes Control and Complications Trial Research Group. Diabetes. 1997 Feb;46(2):271-86.
citation: Cryer PE. The barrier of hypoglycemia in diabetes. Diabetes. 2008 Dec;57(12):3169-76. doi: 10.2337/db08-1084. No abstract available.
citation: Cryer PE. Mechanisms of hypoglycemia-associated autonomic failure in diabetes. N Engl J Med. 2013 Jul 25;369(4):362-72. doi: 10.1056/NEJMra1215228. No abstract available.
citation: Geddes J, Schopman JE, Zammitt NN, Frier BM. Prevalence of impaired awareness of hypoglycaemia in adults with Type 1 diabetes. Diabet Med. 2008 Apr;25(4):501-4. doi: 10.1111/j.1464-5491.2008.02413.x.
citation: Cranston I, Lomas J, Maran A, Macdonald I, Amiel SA. Restoration of hypoglycaemia awareness in patients with long-duration insulin-dependent diabetes. Lancet. 1994 Jul 30;344(8918):283-7. doi: 10.1016/s0140-6736(94)91336-6.
citation: Dagogo-Jack S, Rattarasarn C, Cryer PE. Reversal of hypoglycemia unawareness, but not defective glucose counterregulation, in IDDM. Diabetes. 1994 Dec;43(12):1426-34. doi: 10.2337/diab.43.12.1426.
citation: Rickels MR, Peleckis AJ, Markmann E, Dalton-Bakes C, Kong SM, Teff KL, Naji A. Long-Term Improvement in Glucose Control and Counterregulation by Islet Transplantation for Type 1 Diabetes. J Clin Endocrinol Metab. 2016 Nov;101(11):4421-4430. doi: 10.1210/jc.2016-1649. Epub 2016 Aug 29.
citation: Szepietowska B, Zhu W, Chan O, Horblitt A, Dziura J, Sherwin RS. Modulation of beta-adrenergic receptors in the ventromedial hypothalamus influences counterregulatory responses to hypoglycemia. Diabetes. 2011 Dec;60(12):3154-8. doi: 10.2337/db11-0432. Epub 2011 Oct 19.
citation: Chan O, Sherwin R. Influence of VMH fuel sensing on hypoglycemic responses. Trends Endocrinol Metab. 2013 Dec;24(12):616-24. doi: 10.1016/j.tem.2013.08.005. Epub 2013 Sep 21.
citation: Barnes MB, Lawson MA, Beverly JL. Rate of fall in blood glucose and recurrent hypoglycemia affect glucose dynamics and noradrenergic activation in the ventromedial hypothalamus. Am J Physiol Regul Integr Comp Physiol. 2011 Dec;301(6):R1815-20. doi: 10.1152/ajpregu.00171.2011. Epub 2011 Sep 28.
citation: Ramanathan R, Cryer PE. Adrenergic mediation of hypoglycemia-associated autonomic failure. Diabetes. 2011 Feb;60(2):602-6. doi: 10.2337/db10-1374.
citation: UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. UK Prospective Diabetes Study Group. BMJ. 1998 Sep 12;317(7160):713-20.
citation: Barnett AH, Leslie D, Watkins PJ. Can insulin-treated diabetics be given beta-adrenergic blocking drugs? Br Med J. 1980 Apr 5;280(6219):976-8. doi: 10.1136/bmj.280.6219.976.
citation: Shorr RI, Ray WA, Daugherty JR, Griffin MR. Antihypertensives and the risk of serious hypoglycemia in older persons using insulin or sulfonylureas. JAMA. 1997 Jul 2;278(1):40-3.
citation: Kerr D, MacDonald IA, Heller SR, Tattersall RB. Beta-adrenoceptor blockade and hypoglycaemia. A randomised, double-blind, placebo controlled comparison of metoprolol CR, atenolol and propranolol LA in normal subjects. Br J Clin Pharmacol. 1990 Jun;29(6):685-93. doi: 10.1111/j.1365-2125.1990.tb03689.x.
citation: Viberti GC, Keen H, Bloom SR. Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal response to insulin-induced hypoglycemia in normal subjects. Metabolism. 1980 Sep;29(9):866-72. doi: 10.1016/0026-0495(80)90126-2.
citation: Marengo C, Marena S, Renzetti A, Mossino M, Pagano G. Beta-blockers in hypertensive non-insulin-dependent diabetics: comparison between penbutolol and propranolol on metabolic control and response to insulin-induced hypoglycemia. Acta Diabetol Lat. 1988 Apr-Jun;25(2):141-8. doi: 10.1007/BF02581378.
citation: Clausen-Sjobom N, Lins PE, Adamson U, Curstedt T, Hamberger B. Effects of metoprolol on the counter-regulation and recognition of prolonged hypoglycemia in insulin-dependent diabetics. Acta Med Scand. 1987;222(1):57-63. doi: 10.1111/j.0954-6820.1987.tb09929.x.
citation: Odugbesan O, Toop M, Barnett AH. Beta-and alpha-adrenergic blockade and metabolic responses to insulin induced hypoglycaemia in diabetics. Diabetes Res. 1987 Jul;5(3):135-8.