Advertisement

Current Diabetes Reports

, 19:97 | Cite as

Novel Preparations of Glucagon for the Prevention and Treatment of Hypoglycemia

  • Colin P. Hawkes
  • Diva D. De Leon
  • Michael R. RickelsEmail author
Therapies and New Technologies in the Treatment of Diabetes (M Pietropaolo, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Therapies and New Technologies in the Treatment of Diabetes

Abstract

Purpose of Review

New more stable formulations of glucagon have recently become available, and these provide an opportunity to expand the clinical roles of this hormone in the prevention and management of insulin-induced hypoglycemia. This is applicable in type 1 diabetes, hyperinsulinism, and alimentary hypoglycemia. The aim of this review is to describe these new formulations of glucagon and to provide an overview of current and future therapeutic opportunities that these may provide.

Recent Findings

Four main categories of glucagon formulation have been studied: intranasal glucagon, biochaperone glucagon, dasiglucagon, and non-aqueous soluble glucagon. All four have demonstrated similar glycemic responses to standard glucagon formulations when administered during hypoglycemia. In addition, potential roles of these formulations in the management of congenital hyperinsulinism, alimentary hypoglycemia, and exercise-induced hypoglycemia in type 1 diabetes have been described.

Summary

As our experience with newer glucagon preparations increases, the role of glucagon is likely to expand beyond the emergency use that this medication has been limited to in the past. The innovations described in this review likely represent early examples of a pending large repertoire of indications for stable glucagon.

Keywords

Glucagon Hypoglycemia Diabetes Hyperinsulinism Alimentary Formulation 

Abbreviations

T1D

Type 1 diabetes

GLP-1

Glucagon-like peptide

HAAF

Hypoglycemia-associated autonomic failure

Notes

Funding

Michael R. Rickels is supported in part by Public Health Service Research Grant R01 DK091331. Diva D. De Leon is supported in part by Public Health Service Research Grants R01 DK056268 and R01 DK098517.

Compliance with Ethical Standards

Conflict of Interest

Colin P. Hawkes declares that he has no conflict of interest.

Diva D. De Leon reports grants from National Institute of Health, during the conduct of the study, grants and personal fees from Zealand Pharma A/S, grants and personal fees from Crinetics, personal fees from Soleno Therapeutics, non-financial support from Dexcom, personal fees from Novartis Pharmaceuticals, personal fees from NovoNordisk, personal fees from Xoma Corporation, personal fees from ProSciento, other from Merck, outside the submitted work.

Michael R. Rickels reports grants from National Institutes of Health, during the conduct of the study, grants and personal fees from Xeris Pharmaceuticals and personal fees from Hua Medicine, outside the submitted work.

Human and Animal Rights and Informed Consent

All procedures performed in studies conducted by the authors involving human participants were in accordance with the ethical standards of the University of Pennsylvania or Children’s Hospital of Philadelphia Institutional Review Boards and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.
    Schwartz NS, Clutter WE, Shah SD, Cryer PE. Glycemic thresholds for activation of glucose counterregulatory systems are higher than the threshold for symptoms. J Clin Invest. 1987;79(3):777–81.  https://doi.org/10.1172/JCI112884.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Abraham MB, Jones TW, Naranjo D, Karges B, Oduwole A, Tauschmann M, et al. ISPAD clinical practice consensus guidelines 2018: assessment and management of hypoglycemia in children and adolescents with diabetes. Pediatr Diabetes. 2018;19(Suppl 27):178–92.  https://doi.org/10.1111/pedi.12698.CrossRefPubMedGoogle Scholar
  3. 3.
    • Hawkes CP, Lado JJ, Givler S, De Leon DD. The effect of continuous intravenous glucagon on glucose requirements in infants with congenital hyperinsulinism. JIMD rep. 2019;45:45–50.  https://doi.org/10.1007/8904_2018_140. This study demonstrates the effect of a continuous intravenous glucagon infusion on glucose requirement on infants with congenital hyperinsulinism.CrossRefPubMedGoogle Scholar
  4. 4.
    Salehi M, Vella A, McLaughlin T, Patti ME. Hypoglycemia after gastric bypass surgery: current concepts and controversies. J Clin Endocrinol Metab. 2018;103(8):2815–26.  https://doi.org/10.1210/jc.2018-00528.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Kedia N. Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approach. Diabetes Metab Syndr Obes. 2011;4:337–46.  https://doi.org/10.2147/DMSO.S20633.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Harris G, Diment A, Sulway M, Wilkinson M. Glucagon administration – underevaluated and undertaught. Practical Diabetes Int. 2001;18(1):22–5.  https://doi.org/10.1002/pdi.138.CrossRefGoogle Scholar
  7. 7.
    Rickels MR, Schutta MH, Mueller R, Kapoor S, Markmann JF, Naji A, et al. Glycemic thresholds for activation of counterregulatory hormone and symptom responses in islet transplant recipients. J Clin Endocrinol Metab. 2007;92(3):873–9.  https://doi.org/10.1210/jc.2006-2426.CrossRefGoogle Scholar
  8. 8.
    De Feo P, Perriello G, Torlone E, Ventura MM, Fanelli C, Santeusanio F, et al. Contribution of cortisol to glucose counterregulation in humans. Am J Phys. 1989;257(1 Pt 1):E35–42.Google Scholar
  9. 9.
    De Feo P, Perriello G, Torlone E, Ventura MM, Santeusanio F, Brunetti P, et al. Demonstration of a role for growth hormone in glucose counterregulation. Am J Phys. 1989;256(6 Pt 1):E835–43.Google Scholar
  10. 10.
    Cryer PE. Minireview: glucagon in the pathogenesis of hypoglycemia and hyperglycemia in diabetes. Endocrinology. 2012;153(3):1039–48.  https://doi.org/10.1210/en.2011-1499.CrossRefPubMedGoogle Scholar
  11. 11.
    Hawkes CP, Grimberg A, Dzata VE, De Leon DD. Adding glucagon-stimulated GH testing to the diagnostic fast increases the detection of GH-sufficient children. Horm Res Paediatr. 2016;85:265–72.  https://doi.org/10.1159/000444678.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Hawkes CP, Mavinkurve M, Fallon M, Grimberg A, Cody DC. Serial GH measurement after IV placement alone can detect levels above stimulation test thresholds in children. J Clin Endocrinol Metab. 2015:jc20153102. doi: https://doi.org/10.1210/jc.2015-3102.CrossRefGoogle Scholar
  13. 13.
    Cooperberg BA, Cryer PE. Insulin reciprocally regulates glucagon secretion in humans. Diabetes. 2010;59(11):2936–40.  https://doi.org/10.2337/db10-0728.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Heller SR, Cryer PE. Reduced neuroendocrine and symptomatic responses to subsequent hypoglycemia after 1 episode of hypoglycemia in nondiabetic humans. Diabetes. 1991;40(2):223–6.CrossRefPubMedGoogle Scholar
  15. 15.
    Dagogo-Jack SE, Craft S, Cryer PE. Hypoglycemia-associated autonomic failure in insulin-dependent diabetes mellitus. Recent antecedent hypoglycemia reduces autonomic responses to, symptoms of, and defense against subsequent hypoglycemia. J Clin Invest. 1993;91(3):819–28.  https://doi.org/10.1172/JCI116302.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Davis SN, Mann S, Galassetti P, Neill RA, Tate D, Ertl AC, et al. Effects of differing durations of antecedent hypoglycemia on counterregulatory responses to subsequent hypoglycemia in normal humans. Diabetes. 2000;49(11):1897–903.CrossRefPubMedGoogle Scholar
  17. 17.
    Rickels MR. Hypoglycemia associated autonomic failure, counterregulatory responses, and therapeutic options in type 1 diabetes. Ann N Y Acad Sci. 2019.  https://doi.org/10.1111/nyas.14214.
  18. 18.
    Hirsch IB, Marker JC, Smith LJ, Spina RJ, Parvin CA, Holloszy JO, et al. Insulin and glucagon in prevention of hypoglycemia during exercise in humans. Am J Phys. 1991;260(5 Pt 1):E695–704.  https://doi.org/10.1152/ajpendo.1991.260.5.E695.CrossRefGoogle Scholar
  19. 19.
    Mallad A, Hinshaw L, Schiavon M, Dalla Man C, Dadlani V, Basu R, et al. Exercise effects on postprandial glucose metabolism in type 1 diabetes: a triple-tracer approach. Am J Physiol Endocrinol Metab. 2015;308(12):E1106–15.  https://doi.org/10.1152/ajpendo.00014.2015.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Francescato MP, Stel G, Stenner E, Geat M. Prolonged exercise in type 1 diabetes: performance of a customizable algorithm to estimate the carbohydrate supplements to minimize glycemic imbalances. PLoS One. 2015;10(4):e0125220.  https://doi.org/10.1371/journal.pone.0125220.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Galassetti P, Tate D, Neill RA, Morrey S, Wasserman DH, Davis SN. Effect of antecedent hypoglycemia on counterregulatory responses to subsequent euglycemic exercise in type 1 diabetes. Diabetes. 2003;52(7):1761–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Galassetti P, Tate D, Neill RA, Richardson A, Leu SY, Davis SN. Effect of differing antecedent hypoglycemia on counterregulatory responses to exercise in type 1 diabetes. Am J Physiol Endocrinol Metab. 2006;290(6):E1109–17.  https://doi.org/10.1152/ajpendo.00244.2005.CrossRefPubMedGoogle Scholar
  23. 23.
    Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN. Acute, same-day effects of antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes mellitus. Am J Physiol Endocrinol Metab. 2006;290(6):E1331–8.  https://doi.org/10.1152/ajpendo.00283.2005.CrossRefPubMedGoogle Scholar
  24. 24.
    Sandoval DA, Guy DL, Richardson MA, Ertl AC, Davis SN. Effects of low and moderate antecedent exercise on counterregulatory responses to subsequent hypoglycemia in type 1 diabetes. Diabetes. 2004;53(7):1798–806.CrossRefPubMedGoogle Scholar
  25. 25.
    Davey RJ, Howe W, Paramalingam N, Ferreira LD, Davis EA, Fournier PA, et al. The effect of midday moderate-intensity exercise on postexercise hypoglycemia risk in individuals with type 1 diabetes. J Clin Endocrinol Metab. 2013;98(7):2908–14.  https://doi.org/10.1210/jc.2013-1169.CrossRefPubMedGoogle Scholar
  26. 26.
    Tsalikian E, Mauras N, Beck RW, Tamborlane WV, Janz KF, Chase HP, et al. Impact of exercise on overnight glycemic control in children with type 1 diabetes mellitus. J Pediatr. 2005;147(4):528–34.  https://doi.org/10.1016/j.jpeds.2005.04.065.CrossRefPubMedGoogle Scholar
  27. 27.
    Adzick NS, De Leon DD, States LJ, Lord K, Bhatti TR, Becker SA, et al. Surgical treatment of congenital hyperinsulinism: results from 500 pancreatectomies in neonates and children. J Pediatr Surg. 2019;54(1):27–32.  https://doi.org/10.1016/j.jpedsurg.2018.10.030.CrossRefPubMedGoogle Scholar
  28. 28.
    Neylon OM, Moran MM, Pellicano A, Nightingale M, O'Connell MA. Successful subcutaneous glucagon use for persistent hypoglycaemia in congenital hyperinsulinism. J Pediatr Endocrinol Metab. 2013;26(11–12):1157–61.  https://doi.org/10.1515/jpem-2013-0115.CrossRefPubMedGoogle Scholar
  29. 29.
    Mohnike K, Blankenstein O, Pfuetzner A, Potzsch S, Schober E, Steiner S, et al. Long-term non-surgical therapy of severe persistent congenital hyperinsulinism with glucagon. Horm Res. 2008;70(1):59–64.  https://doi.org/10.1159/000129680.CrossRefPubMedGoogle Scholar
  30. 30.
    Ferrara C, Patel P, Becker S, Stanley CA, Kelly A. Biomarkers of insulin for the diagnosis of Hyperinsulinemic hypoglycemia in infants and children. J Pediatr. 2016;168:212–9.  https://doi.org/10.1016/j.jpeds.2015.09.045.CrossRefPubMedGoogle Scholar
  31. 31.
    Hussain K, Bryan J, Christesen HT, Brusgaard K, Aguilar-Bryan L. Serum glucagon counterregulatory hormonal response to hypoglycemia is blunted in congenital hyperinsulinism. Diabetes. 2005;54(10):2946–51.CrossRefPubMedGoogle Scholar
  32. 32.
    Kefurt R, Langer FB, Schindler K, Shakeri-Leidenmuhler S, Ludvik B, Prager G. Hypoglycemia after Roux-En-Y gastric bypass: detection rates of continuous glucose monitoring (CGM) versus mixed meal test. Surg Obes Relat Dis. 2015;11(3):564–9.  https://doi.org/10.1016/j.soard.2014.11.003.CrossRefPubMedGoogle Scholar
  33. 33.
    Goldfine AB, Patti ME. How common is hypoglycemia after gastric bypass? Obesity (Silver Spring). 2016;24(6):1210–1.  https://doi.org/10.1002/oby.21520.CrossRefGoogle Scholar
  34. 34.
    Salehi M, Prigeon RL, D'Alessio DA. Gastric bypass surgery enhances glucagon-like peptide 1-stimulated postprandial insulin secretion in humans. Diabetes. 2011;60(9):2308–14.  https://doi.org/10.2337/db11-0203.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Bradley D, Conte C, Mittendorfer B, Eagon JC, Varela JE, Fabbrini E, et al. Gastric bypass and banding equally improve insulin sensitivity and beta cell function. J Clin Invest. 2012;122(12):4667–74.  https://doi.org/10.1172/JCI64895.CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Goldfine AB, Mun EC, Devine E, Bernier R, Baz-Hecht M, Jones DB, et al. Patients with neuroglycopenia after gastric bypass surgery have exaggerated incretin and insulin secretory responses to a mixed meal. J Clin Endocrinol Metab. 2007;92(12):4678–85.CrossRefPubMedGoogle Scholar
  37. 37.
    Salehi M, Gastaldelli A, D'Alessio DA. Blockade of glucagon-like peptide 1 receptor corrects postprandial hypoglycemia after gastric bypass. Gastroenterology. 2014;146(3):669–80 e2.  https://doi.org/10.1053/j.gastro.2013.11.044.CrossRefPubMedGoogle Scholar
  38. 38.
    Salehi M, Gastaldelli A, D'Alessio DA. Altered islet function and insulin clearance cause hyperinsulinemia in gastric bypass patients with symptoms of postprandial hypoglycemia. J Clin Endocrinol Metab. 2014;99(6):2008–17.  https://doi.org/10.1210/jc.2013-2686.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Service GJ, Thompson GB, Service FJ, Andrews JC, Collazo-Clavell ML, Lloyd RV. Hyperinsulinemic hypoglycemia with nesidioblastosis after gastric-bypass surgery. N Engl J Med. 2005;353(3):249–54.  https://doi.org/10.1056/NEJMoa043690.CrossRefPubMedGoogle Scholar
  40. 40.
    Calabria AC, Gallagher PR, Simmons R, Blinman T, De Leon DD. Postoperative surveillance and detection of postprandial hypoglycemia after fundoplasty in children. J Pediatr. 2011;159(4):597–601 e1.  https://doi.org/10.1016/j.jpeds.2011.03.049.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Tharakan G, Behary P, Wewer Albrechtsen NJ, Chahal H, Kenkre J, Miras AD, et al. Roles of increased glycaemic variability, GLP-1 and glucagon in hypoglycaemia after Roux-en-Y gastric bypass. Eur J Endocrinol. 2017;177(6):455–64.  https://doi.org/10.1530/EJE-17-0446.CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Maruyama H, Hisatomi A, Orci L, Grodsky GM, Unger RH. Insulin within islets is a physiologic glucagon-release inhibitor. J Clin Invest. 1984;74(6):2296–9.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Toft-Nielsen M, Madsbad S, Holst JJ. Exaggerated secretion of glucagon-like peptide-1 (GLP-1) could cause reactive hypoglycaemia. Diabetologia. 1998;41(10):1180–6.CrossRefPubMedGoogle Scholar
  44. 44.
    Rickels MR, Naji A. Reactive hypoglycaemia following GLP-1 infusion in pancreas transplant recipients. Diabetes Obes Metab. 2010;12(8):731–3.  https://doi.org/10.1111/j.1463-1326.2010.01208.x.CrossRefPubMedGoogle Scholar
  45. 45.
    Abrahamsson N, Borjesson JL, Sundbom M, Wiklund U, Karlsson FA, Eriksson JW. Gastric bypass reduces symptoms and hormonal responses in hypoglycemia. Diabetes. 2016;65(9):2667–75.  https://doi.org/10.2337/db16-0341.CrossRefPubMedGoogle Scholar
  46. 46.
    Steiner SS, Li M, Hauser R, Pohl R. Stabilized glucagon formulation for bihormonal pump use. J Diabetes Sci Technol. 2010;4(6):1332–7.  https://doi.org/10.1177/193229681000400606.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Food and Drug Administration. GlucaGen. NDA 20–918/S-012. 2004. https://www.accessdata.fda.gov/drugsatfda_docs/label/2004/20918s012lbl.pdf. Accessed 03/09/2019.
  48. 48.
    Food and Drug Administration. Glucagon for Injection. NDA 20–928. 1999. https://www.accessdata.fda.gov/drugsatfda_docs/nda/98/20928.pdf. Accessed 03/09/2019.
  49. 49.
    Ghodke S, Nielsen SB, Christiansen G, Hjuler HA, Flink J, Otzen D. Mapping out the multistage fibrillation of glucagon. FEBS J. 2012;279(5):752–65.  https://doi.org/10.1111/j.1742-4658.2011.08465.x.CrossRefPubMedGoogle Scholar
  50. 50.
    Pedersen JS. The nature of amyloid-like glucagon fibrils. J Diabetes Sci Technol. 2010;4(6):1357–67.  https://doi.org/10.1177/193229681000400609.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Taleb N, Haidar A, Messier V, Gingras V, Legault L, Rabasa-Lhoret R. Glucagon in artificial pancreas systems: potential benefits and safety profile of future chronic use. Diabetes Obes Metab. 2017;19(1):13–23.  https://doi.org/10.1111/dom.12789.CrossRefPubMedGoogle Scholar
  52. 52.
    Hovelmann U, Bysted BV, Mouritzen U, Macchi F, Lamers D, Kronshage B, et al. Pharmacokinetic and pharmacodynamic characteristics of dasiglucagon, a novel soluble and stable glucagon analog. Diabetes Care. 2018;41(3):531–7.  https://doi.org/10.2337/dc17-1402.CrossRefPubMedGoogle Scholar
  53. 53.
    Glezer S, Hovelmann U, Teng S, Lamers D, Odoul M, Correia J, et al. BioChaperone glucagon (BCG), a stable ready-to-use liquid glucagon formulation, is well tolerated and quickly restores euglycemia after insulin-induced hypoglycemia. Diabetes. 2018;67(Supplement 1):305–OR.  https://doi.org/10.2337/db18-305-OR.CrossRefGoogle Scholar
  54. 54.
    Castle JR, Youssef JE, Branigan D, Newswanger B, Strange P, Cummins M, et al. Comparative pharmacokinetic/pharmacodynamic study of liquid stable glucagon versus lyophilized glucagon in type 1 diabetes subjects. J Diabetes Sci Technol. 2016;10(5):1101–7.  https://doi.org/10.1177/1932296816653141.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Haymond MW, DuBose SN, Rickels MR, Wolpert H, Shah VN, Sherr JL, et al. Efficacy and safety of mini-dose glucagon for treatment of nonsevere hypoglycemia in adults with type 1 diabetes. J Clin Endocrinol Metab. 2017;102(8):2994–3001.  https://doi.org/10.1210/jc.2017-00591.CrossRefPubMedGoogle Scholar
  56. 56.
    • Rickels MR, Ruedy KJ, Foster NC, Piche CA, Dulude H, Sherr JL, et al. Intranasal glucagon for treatment of insulin-induced hypoglycemia in adults with type 1 diabetes: a randomized crossover noninferiority study. Diabetes Care. 2016;39(2):264–70.  https://doi.org/10.2337/dc15-1498. In this study, the authors demonstrate the comparable efficacy of intranasal glucagon with standard intramuscular glucagon in managing hypoglycemia in patients with type 1 diabetes.CrossRefPubMedGoogle Scholar
  57. 57.
    Meiffren G, Teng S, Ranson A, Gaudier M, Duracher D, Soula R et al. Preclinical efficacy of a stable aqueous formulation of human glucagon with BioChaperone Technology (BC GLU). American Diabetes Association 77th Scientific Sessions; San Diego, CA 2017. p. 1150-P.Google Scholar
  58. 58.
    Wilson LM, Castle JR. Stable liquid glucagon: beyond emergency hypoglycemia rescue. J Diabetes Sci Technol. 2018;12(4):847–53.  https://doi.org/10.1177/1932296818757795.CrossRefPubMedPubMedCentralGoogle Scholar
  59. 59.
    Ranson A, Hövelmann U, Seroussi C, Lamers D, Correia J, Zijlstra E et al. Biochaperone glucagon, a stable ready-to-use liquid glucagon formulation enabled by biochaperone technology, is well tolerated and quickly restores euglycemia after insulin-induced hypoglycemia. Advanced Technologies & Treatment for Diabetes; 20–23 February 2019; Berlin, Germany 2019.Google Scholar
  60. 60.
    A trial to investigate the safety and the pharmacokinetic, pharmacodynamic characteristics of two BioChaperone® glucagon formulations compared to marketed GlucaGen® in Subjects With T1DM. https://ClinicalTrials.gov/show/NCT03176524.
  61. 61.
    Newswanger B, Ammons S, Phadnis N, Ward WK, Castle J, Campbell RW, et al. Development of a highly stable, nonaqueous glucagon formulation for delivery via infusion pump systems. J Diabetes Sci Technol. 2015;9(1):24–33.  https://doi.org/10.1177/1932296814565131.CrossRefPubMedPubMedCentralGoogle Scholar
  62. 62.
    Cersosimo E, Cummins MJ, Kinzell JH, Michalek J, Newswanger BJ, Prestrelski SJ, et al. A phase 2 comparative safety PK/PD study of stable nonaqueous glucagon (g-Pen) vs. Lilly glucagon for treatment of severe hypoglycemia. Diabetes Care. 2014;63(Supplement 1A):LB1.Google Scholar
  63. 63.
    Pontiroli AE. Intranasal glucagon: a promising approach for treatment of severe hypoglycemia. J Diabetes Sci Technol. 2015;9(1):38–43.  https://doi.org/10.1177/1932296814557518.CrossRefGoogle Scholar
  64. 64.
    Locemia Solutions ULC. Safety and efficacy of a novel glucagon formulation in type 1 diabetic patients following insulin-induced hypoglycemia (AMG102). https://clinicaltrials.gov/ct2/show/results/NCT01556594. Accessed 03/13/19 2019.
  65. 65.
    Food and Drug Administration. BAQSIMI (glucagon) nasal powder. NDA 210134. 2019. https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/210134s000lbl.pdf. Accessed 30 Aug 2019.
  66. 66.
    Palylyk-Colwell E, Ford C. A transdermal glucagon patch for severe hypoglycemia. CADTH Issues in Emerging Health Technologies. Ottawa (ON)2016. p. 1–7.Google Scholar
  67. 67.
    Safety and efficacy of ZP-glucagon to injectable glucagon for hypoglycemia. https://ClinicalTrials.gov/show/NCT02459938.
  68. 68.
    Hompesch M, Grosjean P, Morrow L, Hijazi Y, Ishibai M, Teichert L et al. 1066-P / 1066 - The novel glucagon receptor agonist SAR438544, first in human safety, pharmacokinetic, and pharmacodynamic data from a study in healthy volunteers. American Diabetes Association 77th Scientific Sessions; 2017; San Diego 2017.Google Scholar
  69. 69.
  70. 70.
    Uribe-Bruce L, Morrow L, Canney L, Pichotta P, Hompesch M, Krasner A et al. Pharmacokinetic (Pk) and pharmacodynamic (PD) profiles of BiOD-961 compared with marketed glucagons. American Diabetes Association 2015.Google Scholar
  71. 71.
    • Haymond MW, Schreiner B. Mini-dose glucagon rescue for hypoglycemia in children with type 1 diabetes. Diabetes Care. 2001;24(4):643–5. This seminal study established the mini-dose glucagon approach to managing impending hypoglycemia in pediatric patients with type 1 diabetes.CrossRefPubMedGoogle Scholar
  72. 72.
    Haymond MW, Redondo MJ, McKay S, Cummins MJ, Newswanger B, Kinzell J, et al. Nonaqueous, mini-dose glucagon for treatment of mild hypoglycemia in adults with type 1 diabetes: a dose-seeking study. Diabetes Care. 2016;39(3):465–8.  https://doi.org/10.2337/dc15-2124.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    • Rickels MR, DuBose SN, Toschi E, Beck RW, Verdejo AS, Wolpert H, et al. Mini-dose glucagon as a novel approach to prevent exercise-induced hypoglycemia in type 1 diabetes. Diabetes Care. 2018;41(9):1909–16.  https://doi.org/10.2337/dc18-0051. This is the first study to demonstrate effective prevention of exercise-induced hypogylcemia with mini-dose glucagon when compared to insulin reduction and glucose ingestion in individuals with type 1 diabetes.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Hovelmann U, Olsen MB, Mouritzen U, Lamers D, Kronshage B, Heise T. Low doses of dasiglucagon consistently increase plasma glucose levels from hypoglycaemia and euglycaemia in people with type 1 diabetes mellitus. Diabetes Obes Metab. 2019;21(3):601–10.  https://doi.org/10.1111/dom.13562.CrossRefPubMedGoogle Scholar
  75. 75.
    Steineck IIK, Ranjan A, Schmidt S, Clausen TR, Holst JJ, Norgaard K. Preserved glucose response to low-dose glucagon after exercise in insulin-pump-treated individuals with type 1 diabetes: a randomised crossover study. Diabetologia. 2019;62(4):582–92.  https://doi.org/10.1007/s00125-018-4807-8.CrossRefPubMedGoogle Scholar
  76. 76.
    Yale JF, Dulude H, Egeth M, Piche CA, Lafontaine M, Carballo D, et al. Faster use and fewer failures with needle-free nasal glucagon versus injectable glucagon in severe hypoglycemia rescue: a simulation study. Diabetes Technol Ther. 2017;19(7):423–32.  https://doi.org/10.1089/dia.2016.0460.CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    Sherr JL, Ruedy KJ, Foster NC, Piche CA, Dulude H, Rickels MR, et al. Glucagon nasal powder: a promising alternative to intramuscular glucagon in youth with type 1 diabetes. Diabetes Care. 2016;39(4):555–62.  https://doi.org/10.2337/dc15-1606.CrossRefPubMedPubMedCentralGoogle Scholar
  78. 78.
    Haidar A, Rabasa-Lhoret R, Legault L, Lovblom LE, Rakheja R, Messier V, et al. Single- and dual-hormone artificial pancreas for overnight glucose control in type 1 diabetes. J Clin Endocrinol Metab. 2016;101(1):214–23.  https://doi.org/10.1210/jc.2015-3003.CrossRefPubMedGoogle Scholar
  79. 79.
    The bihormonal ilet bionic pancreas feasibility study. https://ClinicalTrials.gov/show/NCT03840278.
  80. 80.
    Glucagon infusion in T1D patients with recurrent severe hypoglycemia: effects on counterregulatory responses. https://clinicaltrials.gov/ct2/show/NCT03490942.
  81. 81.
    Thornton P, Truong L, Reynolds C, Rodriguez L, Cummins M, Junaidi K. Continuous infusion of subcutaneous ready-to-use stable liquid glucagon has similar efficacy to intravenous reconstituted glucagon in children with congenital hyperinsulinism. Pediatric Academic Society; Baltimore, MD 2019.Google Scholar
  82. 82.
    Open-label trial evaluating efficacy and safety of dasiglucagon in children with congenital hyperinsulinism. https://ClinicalTrials.gov/show/NCT03777176.
  83. 83.
    CSI-glucagon for prevention of hypoglycemia in children with congenital hyperinsulinism. https://ClinicalTrials.gov/show/NCT02937558.
  84. 84.
    Laguna Sanz AJ, Mulla CM, Fowler KM, Cloutier E, Goldfine AB, Newswanger B, et al. Design and clinical evaluation of a novel low-glucose prediction algorithm with mini-dose stable glucagon delivery in post-bariatric hypoglycemia. Diabetes Technol Ther. 2018;20(2):127–39.  https://doi.org/10.1089/dia.2017.0298.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Colin P. Hawkes
    • 1
    • 2
  • Diva D. De Leon
    • 1
    • 2
    • 3
  • Michael R. Rickels
    • 2
    • 3
    • 4
    Email author
  1. 1.Division of Endocrinology and Diabetes, Department of PediatricsThe Children’s Hospital of PhiladelphiaPhiladelphiaUSA
  2. 2.Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Institute for Diabetes, Obesity & Metabolism, Perelman School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  4. 4.Division of Endocrinology, Diabetes & Metabolism, Department of MedicineHospital of the University of PennsylvaniaPhiladelphiaUSA

Personalised recommendations