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 Table of Contents  
REVIEW ARTICLES
Year : 2021  |  Volume : 12  |  Issue : 2  |  Page : 114-119

Inhaled glucagon: A new hope for severe hypoglycemia in type 1 diabetes


Department of Pharmacy Practice, Deccan School of Pharmacy, Hyderabad, Telangana, India

Date of Submission27-Apr-2020
Date of Decision27-May-2020
Date of Acceptance20-Jun-2020
Date of Web Publication31-Mar-2021

Correspondence Address:
Salva Fatima Heba
Department of Pharmacy Practice, Deccan School of Pharmacy, Darussalam, Aghapura, Hyderabad 500002, Telangana.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jod.jod_26_20

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  Abstract 

Until now injectable glucagon was the only available treatment used in the management of severe hypoglycemia wherein glucagon had to be prepared in several steps before administration. This method of delivery of injectable glucagon being cumbersome and unappealing for a wide majority of the patients had led to a search for an alternative route of drug delivery. Intranasal (IN) glucagon now serves an efficient, safe, easy to administer, and a favorable substitute to glucagon injections. This ready-to-use device stands in clear contrast to overcome the limitations associated with the currently available glucagon preparations, which has emerged a key advancement in the management of severe hypoglycemia in adolescents and children with type 1 diabetes. IN glucagon is now being developed and studied in other countries as well to meet the unmet need for an easy and convenient glucagon administration. This review covers the basic information of nasal glucagon, trials on nasal glucagon in children’s and adults, and its potential uses, limitations, and future scope in practice.

Keywords: Cumbersome, hypoglycemia, injectable glucagon, intranasal glucagon, management


How to cite this article:
Heba SF, Parveen U, Khanum SS, Gulnaaz M, Tabassum M, Safiyya SB. Inhaled glucagon: A new hope for severe hypoglycemia in type 1 diabetes. J Diabetol 2021;12:114-9

How to cite this URL:
Heba SF, Parveen U, Khanum SS, Gulnaaz M, Tabassum M, Safiyya SB. Inhaled glucagon: A new hope for severe hypoglycemia in type 1 diabetes. J Diabetol [serial online] 2021 [cited 2021 Apr 12];12:114-9. Available from: https://www.journalofdiabetology.org/text.asp?2021/12/2/114/312657




  Diabetes: Current Scenario Top


Currently, millions of people suffer from diabetes and approximately 16%–21% of adults with type 2 diabetes receive insulin to maintain normal blood glucose levels;[1] in particular, 30%–60% of insulin-treated patients report symptoms of hypoglycemia.[2] Attaining optimal glycemic control is a key to avoid microvascular diabetes complications[3],[4],[5] but at the expense of severe hypoglycemia leading to cognitive impairment, convulsions or seizures, coma, and death.[3],[6],[8] Severe hypoglycemia as defined by the American Diabetes Association (ADA) is an episode associated with severe cognitive impairment and requires external assistance for recovery.[7] However, hypoglycemia remains a common problem of glucose-lowering agents[8] and severe hypoglycemia being a major complication of insulin therapy acts as a main barrier in achieving optimal glycemic control.[9]

Over a decade, there has been a rise in the incidence of T1DM by 2.5%–3% per year worldwide[10] as well as the number of patients using insulin alone or insulin plus oral hypoglycemic agents[11],[12] and the frequency of hypoglycemia is increasing.[13] Among patients treated with insulin, the frequency of hypoglycemia is lower in type 2 diabetes,[1],[14] but the incidence is higher in both T1 and T2 diabetes patients receiving intensive insulin therapy,[15],[16] notably in elderly[11] with a distinct risk of hypoglycemia contingent on insulin regimens and age.[17] The fear of hypoglycemia itself persists a major deterrent in maintenance of euglycemia in youth having type 1 diabetes, predominantly in children as well as adolescent,[18],[19] and the alarming rates of hypoglycemic events urge that this worry is justified. Both prevention and treatment are essential.[20] Although mild hypoglycemia can be treated with oral carbohydrates ingestion,[21] severe hypoglycemia needs support from an arbiter via the administration of glucose or glucagon through parenteral route.[20],[22],[23],[24]


  Glucagon Top


Glucagon is a polypeptide hormone formed in the pancreas by the α cells of  Islets of Langerhans More Details.[25] Glucagon primarily influences glycogenolysis in liver, and gluconeogenesis, thereby increasing plasma glucose concentrations.[26] It is critical for maintaining homeostasis of liver[27] and has a counter-regulatory effect on insulin to obtain optimal glucose concentrations.[25] In addition, glucagon also has a role in inducing ketogenesis, delaying of intestinal motility, suppression of appetite, lipid, and protein metabolism and might have a greater role in amino-acid metabolism which is yet under evaluation.[28],[29] Glucagon is generally available as intravenous, intramuscular (IM), and subcutaneous (SC) for treatment of severe hypoglycemia in diabetes mellitus and various other clinical uses including radiology, endoscopy, and also as a diagnostic aid. It is mainly used in the treatment of severe hypoglycemia where IM and SC glucagon is the treatment of choice outside clinical setting.[30],[31],[32]


  Problems with Glucagon Top


Glucagon is the only currently available treatment for hypoglycemia outside emergency medical care.[6] Glucagon solutions are highly unstable in aqueous solution because of the tendency to form fibrils leading to loss of activity and increased risk of occlusion of catheters, which in turn could be potentially cytotoxic at high concentrations. Moreover, the commercially available glucagon kits involve reconstitution of lyophilized powders immediately before administration by a caregiver or bystander which are to be used immediately and the remaining is to be discarded immediately.[34],[35],[36] Moreover, the complex preparation and administration process has led in search of alternative routes of glucagon administration. Various studies have shown the drawbacks with the administration of currently available glucagon kits and emergency kits[30],[31],[32],[33],[34],[35],[36] and the need for alternative routes of glucagon delivery is emphasized in a study of injectable glucagon where in approximately half of the caregivers and more than half of the acquaintances failed to deliver any glucagon and three participants delivered insulin instead of glucagon.[36] Also, in a study involving children and adolescents with T1D, approximately 70% of the individuals had difficulty in handling the glucagon emergency kits and a few aborted or injected air or diluent.[35] In addition, a survey conducted showed that nearly 75% of the patients never relied or carried glucagon emergency kits, suggesting its use a complex process.[37] However, the administration is so complex that only trained individuals are preferred for administration making its use a challenging one.


  Intranasal Glucagon Top


Background

Intranasal (IN) glucagon was used early in 1980s wherein IN glucagon drops raised blood glucose levels in healthy subjects.[38] Later on, IN glucagon solution and IN glucagon powder have been shown to have similar effects, with an exception that a promoter was used for absorption.[39],[40],[41],[42] Over the years, several studies reported the efficacy of IN glucagon to treat hypoglycemia, wherein 2 mg of IN glucagon was as effective as 1 mg of IM glucagon,[43] whereas IN route is the most safest method of administration, especially in emergency settings where IV or IM route may not always be desirable.[44],[45] Although it was shown to have favorable results in healthy volunteers, adults, and children with diabetes, at that time the product was never commercialized, probably due to the fact that data on the effectiveness were adequate and also investment issues market might not be able to justify.[46] Only in 2010 efforts were made to develop IN glucagon as a safe and comfortable means of administration of needle-free formulation resulting in the conduct of several studies in support of the safety and efficacy of the product.[35],[36] Successfully, on July 24, 2019, IN glucagon (Baqsimi) by Eli Lilly and Company was approved by US Food and Drug Administration (FDA) in the management of severe hypoglycemia in diabetic patients having age greater than or equal to 4 years, based on three clinical trials, two in adults, and one in children.[47]

IN glucagon represents a novel, needle free, simple to use, potential substitute to injectable glucagon for the management of severe hypoglycemia. In comparison to IM glucagon, IN glucagon resulted in lower blood glucagon levels, whereas the clinical effects of raising glucose levels were similar to injectable glucagon despite the low doses being delivered.[48] Importantly, a needless portable device with self-administration technique incorporating 3 mg of glucagon powder that do not necessitate prior preparation before administration has emerged a key advancement in the management of severe hypoglycemia in adolescents and children with type 1 diabetes.

Biology

Glucagon is rapidly absorbed through nasal membranes owing to its anatomic and physiologic structure, with peak plasma levels attaining within 15–20 min after administration.[47] However, bioavailability of glucagon and other peptide hormones is lower after IN administration than after IM administration resulting in lower peak plasma concentrations.[49] IN glucagon exerted similar glycemic response as IM glucagon in different studies, wherein IN glucagon in a dose of 2 mg or 3 mg, in the pediatric population with type 1 diabetes was well tolerated and produced a similar glycemic response to weight-based IM glucagon of a dose 0.5 or 1 mg, suggesting that a similar dose can be used in both children and adults having type 1 diabetes, in turn simplifying the medication prescribing over a different age range of patients suffering from type 1 diabetes.[50]

Similarly, a meta-analysis revealed IN glucagon and IM glucagon to be equally effective, without notable differences in glycemic response.[46] Compared to insulin or other peptide hormones, glucagon did not seem to have a clear dose–response relationship, suggesting that glucagon is shown to have saturation. Although IV or IM glucagon has been shown to have a clear dose–response response relationship, on increasing the dose saturation was observed (NDA 020928, Eli Lilly). In addition, the use of nasal decongestants following IN glucagon administration did not have any effect on the pharmacokinetic parameters of glucagon.[47],[51]

Efficacy and safety

Various studies have reported the positive outcomes in terms of effectiveness and safety of 3 mg of nasal glucagon as an alternative to parenteral glucagon in children’s as well as in adults in research trials and outside clinical setting [Table 1]. Moreover, a similar dose could be used in children until 4 years of age.[52] There are many evidence in support of IN glucagon use. In a phase III multicenter, open-label study in children and adolescents having type 1 diabetes, nasal glucagon (3 mg) was administered by trained caregivers wherein hypoglycemic events returned to normal levels within 30 min in all 33 patients following nasal glucagon administration. Most importantly, as reported by caregivers nasal administration resulted in management of nearly 60.6% of events within 30s.[53] Similarly, another study in children with type 1 diabetes, 48 children randomly received 3 mg nasal glucagon and 1 mg IM glucagon based on weight where both the agents showed comparable figures by achieving the desired supraphysiological glucagon response of more than 25 mg/dL after 20 min of dosing. Accordingly levels of plasma glucose were similar in both the groups.[50] In addition, a real-world study evaluated the use of nasal glucagon in the management of hypoglycemia in adults; overall 157 hypoglycemic events were evaluated, of which 151 (96.2%) patients returned to normal status in under 30 min and in 12 patients severe hypoglycemic events were resolved in under 15 min following nasal glucagon administration. However, adverse events were mild in severity.[54] A noninferiority study examined the use of nasal glucagon in type 1 diabetic adults followed by overnight fasting hypoglycemia induced by intravenous insulin and subsequently treated with respective nasal (3 mg) or 1 mg IM glucagon. After only a mean time of 16 min and 13 min, there was a rise in plasma glucose levels up to ≥70 mg/dL following IN administration and ≥20 mg/dL after IM glucagon administration, respectively. Thus, IN glucagon in a 3 mg dose was well tolerated, potent, in treating those adults with insulin-induced hypoglycemia.[49] Importantly, a randomized study evaluated the outcomes of cold and use of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in healthy volunteers. It was found that the PK and PD patterns of glucose and glucagon were almost comparable in both the groups concluding that nasal congestion with or without concomitant decongestant use did not alter the glycemic control.[51] In terms of ease of administration, a study manifested that nasal glucagon administered by nonmedical caregivers also resulted in notable increase in success rate while delivering the full dose when compared to IM glucagon administration.[36]
Table 1: Studies on nasal glucagon

Click here to view



  Nasal Glucagon Use in Patient-centric Care Top


As injectable glucagon is considered as the treatment of choice for hypoglycemia where currently obtainable glucagon emergency kits are unstable and inconvenient,[48],[55] nasal glucagon, a novel drug, can be used as an alternative to IM glucagon owing to easier mode of administration and decreasing the hazards of accidental exposures.[44],[45] Also IN glucagon increases blood glucose levels both in healthy subjects and in subjects with diabetes under normal circumstances as well as during hypoglycemia. Apart from glucose metabolism, nasal glucagon is thought to exert other actions such as induction of gastric hypotonia which is yet under investigation. It has been reported in overweight individuals that nasal glucagon in a dose of 0.7 mg is thought to increase energy expenditure without causing hypoglycemia with no influence on appetite.[56]

Interestingly, glucagon is reported to be useful in neonatal hypoglycemia together with octreotide; it is helpful in counteracting hypoglycemic episodes in congenital hyperinsulnism.[57] In accordance with health-care models, nasal glucagon offers remarkable advantages and is expected to minimize health-care costs, reducing emergency department visits, restricting the necessity of emergency services.[58] In forthcoming days, there is a possibility for increased sales of IN glucagon owing to its easier accessibility, thereby contributing to education in expenses.

Limitations

Although nasal glucagon is useful in treating hypoglycemic events, in real-world practice IN glucagon use is likely to be more cumbersome especially in state of unconsciousness or during seizures.[58] Moreover, it has contraindications in patients suffering from insulinoma or phechromocytoma owing to an exaggerated insulin response in turn causing hypoglycemia. Nasal glucagon relies on glycogen stores to maintain blood glucose levels and as such nasal glucagon might be ineffective in patients with reduced glycogen stores such as in situations of starvation, adrenal insufficiency, or chronic hypoglycemia.[47]

Adverse events widely differed according to the studies probably due to the differences in study conditions and study criteria. Majority of the reported adverse events with nasal glucagon use were of low-to-moderate severity, whereas vomiting, nausea, and upper respiratory tract irritation were the most commonly reported events.[47],[59],[60] Alteration in taste, itching tachycardia, high blood pressure, and upper respiratory tract hypersensitivity events were other adverse events noted in patients receiving nasal glucagon. In addition, nasal glucagon coadministered with β-blockers, indomethacin, and anticholinergic drugs results in inappropriate glycemic response and adverse effects.[47],[59],[60],[61] However, no risk of birth defects has been reported by a number of studies, but its effectiveness in pregnancy and breastfeeding infants remains unclear. Moreover, the efficacy and safety of its use in pediatric above 4 years of age have not been approved yet.[47]


  Future Scope Top


Now that nasal glucagon in a dose of 3 mg has been approved by US FDA, there is an expectation that needleless IN glucagon may ultimately be approved and commercialized in other countries as well to address an important unfilled gap in medical need. The established safety, efficacy, and the convenience of administration with minimal training aids its win over other glucagon preparations currently available in the market. Moreover, in emergency situations of severe hypoglycemia quick administration of glucagon could save time which would make a difference between life and death. IN glucagon once commercialized will find an extensive scope for patients in diabetes care.

At the moment where needle-free glucagon has been shown a hopeful alternative to other available injectable glucagon in type 1 diabetes, additional studies are required to establish the real-world safety as well as the efficacy of these new products within outpatient hypoglycemic events in patients with diabetes. With adequate research and extensive studies, nasal glucagon may also find its place in effective endocrine testing. At present, we await the availability of IN glucagon for use in children’s, adolescents, and adults, lowering the burden of disease in diabetic patients. We hope that nasal glucagon provides a feasible solution to severe hypoglycemia to the ailing need for a glucagon that is needle-free and easy to administer especially in emergencies.


  Conclusion Top


Finally, nasal glucagon, a novel drug, can be effectively used in the treatment of severe hypoglycemia owing to its anonymous unique properties in terms of ease of use and effective mode of delivery, thereby filling the unmet criteria in an emergency situation where its use is warranted. Interestingly, IN glucagon use could further minimize the use of costly efficient emergency facilities, minimizing health-care costs and number of hospitalizations, thereby lowering the commercial strain of hypoglycemia. Eventually, nasal glucagon use should be commercialized as it emphasizes and addresses the foremost unsatisfied medical necessity.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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Diabetes: Curren...
Glucagon
Problems with Gl...
Intranasal Glucagon
Nasal Glucagon U...
Future Scope
Conclusion
References
Article Tables

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