Keywords
Cumbersome - hypoglycemia - injectable glucagon - nasal glucagon - management
The Current Diabetes Scene
The Current Diabetes Scene
Currently, millions of people suffer from diabetes and around 16%–21% of adults with type 2 diabetes (T2D) 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]],[[7]] Severe hypoglycemia, as defined by the American Diabetes Association, is an episode associated with severe cognitive impairment and requires external assistance for recovery.[[8]] However, hypoglycemia remains a common problem of glucose-lowering agents,[[7]] and severe hypoglycemia, being a major complication of insulin therapy, acts as the main barrier in achieving optimal glycemic control.[[9]]Over a decade, there has been a rise in the incidence of Type 1 diabetes (T1D) 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 also raising.[[13]] Among patients treated with insulin, the frequency of hypoglycemia is lower in T2D,[ 1],[[14]] but the incidence is higher in both T1D and T2D patients receiving intensive insulin therapy,[[15]],[[16]] notably in the elderly[[11]] with a distinct risk of hypoglycemia contingent upon insulin regimens and age.[[17]] The fear of hypoglycemia itself persists as a major deterrent in maintenance of euglycemia in youth having T1D, predominantly in children as well as adolescents,[[18]],[[19]] and the alarming rates of hypoglycemic events urge this worry is justified. Both prevention and treatment are essential.[[20]] While mild hypoglycemia can be treated with oral carbohydrate ingestion,[[21]] severe hypoglycemia needs support from an arbiter via the administration of glucose or glucagon through parenteral route.[[20]][[22]],[[23]],[[24]]
Glucagon
Glucagon is a polypeptide hormone formed in the pancreas by the alpha-cells of islets of Langerhans.[[25]] Glucagon primarily influences glycogenolysis in the liver, and gluconeogenesis, thereby increasing plasma glucose concentrations.[[26]] It is critical for maintaining glucose homeostasis of the 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, and 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 (IV), intramuscular (IM), and subcutaneous for treatment of severe hypoglycemia in diabetes and various other clinical uses including radiology and 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
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 the 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.[[33]],[[34]],[[35]] Moreover, the complex preparation and administration process has led to 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,[[6]][[30]],[[31]],[[32]],[[33]],[[34]],[[35]],[[36]] and the need for alternative routes of glucagon delivery is emphasized in a study of injectable glucagon wherein 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.[[35]] Furthermore, 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.[[34]] In addition, a survey showed that nearly 75% of the patients never relied on or carried glucagon emergency kits, suggesting that it is used a complex process.[[37]] However, the administration is so complex that only trained individuals are preferred for administration making its use a challenging one.
Nasal Glucagon
Background
Nasal glucagon was used early in the 1980s, wherein IN glucagon drops raise blood glucose levels in healthy controls.[[38]] Later, nasal glucagon solution and nasal 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 the nasal glucagon to treat hypoglycemia, wherein 2 mg of nasal glucagon was as effective as 1 mg of IM glucagon,[[43]] while nasal route being 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, the product was never commercialized.[[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 conduct of several studies in support of the safety and efficacy of the product.[[35]],[[45]] Successfully, on July 24, 2019, nasal glucagon (Baqsimi) by Eli Lilly and Company was approved by the US Food and Drug Administration (FDA) in the management of severe hypoglycemia in diabetic patients having age ≥4 years, based on 3 clinical trials, 2 in adults, and 1 in children.[[47]]
Nasal 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, nasal glucagon resulted in lower blood glucagon levels whereas the clinical effects of raising glucose levels were like 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 does not necessitate prior preparation before administration has emerged a key advancement in the management of severe hypoglycemia in adolescents and children with T1D.
Biology
Glucagon is rapidly absorbed through nasal membranes owing to its anatomic and physiologic structure, wherein needing enhancers for absorption with peak plasma levels attaining within 15–20 min after administration.[[47]] However, bioavailability of glucagon and other peptide hormones is lower after nasal administration than after IM administration resulting in lower peak plasma concentrations.[[49]] nasal glucagon exerted a similar glycemic response as IM glucagon in different studies, wherein nasal glucagon in a dose of 2 mg or 3 mg in the pediatric population with T1D 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 can be used in both children and adults havingT1D, in turn, simplifying the medication prescribing over a difference age range of patients suffering from T1D.[[50]]
Similarly, a meta-analysis revealed nasal 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. While IV or IM glucagon has been shown to have a clear dose–response relationship, however, upon increasing, the dose saturation was observed (NDA 020928, Eli Lilly). In addition, the use of nasal decongestants following nasal glucagon administration did not have any effect on the pharmacokinetic parameters of glucagon.[[47]],[[51]]
Efficacy and safety
Moreover, a similar dose could be used in children until 4 years of age.[[55]] There are many evidences in support of nasal glucagon use [[Table 1]]. In a Phase III multicenter, open-label study in children and adolescents with T1D, nasal glucagon (3 mg) was administered by trained care givers wherein hypoglycemic events returned to normal levels within 30 min in all 33 patients following nasal glucagon administration. Most importantly, nasal administration resulted in management of nearly 60.6% of events within 30 s as reported by caregivers.[[53]] Similarly, in another study of children with T1D, 48 children randomly received 3 mg nasal glucagon and 1 mg IM glucagon based on weight where both the agents exhibited comparable figures by achieving the desired supraphysiological glucagon response of more than 25 mg/dl after 20 min of dosing. Accordingly, the 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 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. Also adverse events were mild in severity.[[54]] A noninferiority study examined the use of nasal glucagon in T1D adults, following overnight fasting hypoglycemia that was induced by IV 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 nasal administration and ≥20 mg/dL after IM glucagon administration, respectively. Thus, nasal 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.[[35]]
Table 1: Studies on nasal glucagon
Table 1: Contd...
Nasal Glucagon Use in Patient-Centric Care
Nasal Glucagon Use in Patient-Centric Care
As injectable glucagon is considered as the treatment of choice for hypoglycemia where currently obtainable glucagon emergency kits are unstable and inconvenient,[[48]],[[56]] 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]] Furthermore, IN glucagon increases blood glucose levels both in healthy controls as well as in patients with diabetes under normal circumstances as well as during hypoglycemia. Apart from glucose metabolism, nasal glucagon as long exerts other actions such as induction of gastric hypotonia. It has been reported in overweight individuals, and nasal glucagon in a dose of 0.7 mg is thought to increase energy expenditure without causing hypoglycemia with no influence on appetite.[[57]]
Interestingly, glucagon is reported to be useful in neonatal hypoglycemia together with octreotide, and it is helpful in counteracting hypoglycemic episodes in congenital hyperinsulinism.[[58]] 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.[[59]] In forthcoming days, there is a possibility for excessive sales of nasal glucagon owing to its easier accessibility, thereby contributing to reduction in expenses.
Limitations
Although nasal glucagon is useful in treating hypoglycemic events, in real-world practice, nasal glucagon use is likely to be more cumbersome, especially in state of unconsciousness or during seizures.[[59]] Moreover, it has contraindications in patients suffering from insulinoma or pheochromocytoma owing to an exaggerated insulin response, in turn, causing hypoglycemia. Nasal glucagon relies on glycogen stores in order 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 while vomiting, nausea, and upper respiratory tract irritation were the most reported events.[[47]],[[60]],[[61]] 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 co-administered with beta-blockers, indomethacin, and anticholinergic drugs results in inappropriate glycemic response and adverse effects.[[47]],[[52]],[[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
Now that nasal glucagon in a dose of 3 mg has been approved by the US FDA, there is expectation that needle-free nasal glucagon may ultimately be proved and commercialized in other countries as well to address an important gap in medical care. 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. nasal glucagon once commercialized will find an extensive scope for patients in diabetes care.
At the moment where needle-free glucagon has been demonstrated a hopeful alternative to other available injectable glucagon in T1D, additional studies are required in order 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 nasal glucagon for use in children, 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.ConclusionIN glucagon, a novel drug, can be effectively used in the treatment of severe hypoglycemia owing to its numerous unique properties in terms of ease of use, effective mode of delivery, thereby filling the unmet criteria in an emergency situation where its use is warranted. IN glucagon use could further minimize the utilization of costly efficient emergency facilities, minimizing health-care costs and number of hospitalizations, thereby lowering the commercial strain of hypoglycemia. Eventually, IN glucagon use should be commercialized as it emphasizes and addresses the foremost unmet medical necessity.
Authors' contributions
All authors contributed to the conceptualization, research, drafting and revision of article and they all approved its final version.
Compliance with ethical principles
Formal ethical review and approval are not required.
