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.
