Intranasal Glucagon Combats Hypoglycemia in Type 1 Diabetes

Miriam E Tucker

December 29, 2015

An investigational intranasal glucagon product may treat hypoglycemia just as effectively as intramuscular injections, a new study of adults with type 1 diabetes suggests.

The intranasal glucagon product was owned by Locemia Solutions at the time of the study but was acquired by Eli Lilly in October 2015.

The findings were published online December 17 in Diabetes Care by Michael R Rickels, MD, associate professor of medicine at the Hospital of the University of Pennsylvania, Philadelphia, and colleagues.

In the nonblinded study, 75 adults with type 1 diabetes were infused with insulin to induce hypoglycemia and then administered intranasal or intramuscular glucagon. The intranasal formulation's action time lagged just slightly behind that of the intramuscular formulation by about 5 minutes.

That difference is unlikely to be clinically significant and more than offset by the real-world delay and error involved in the administration of intramuscular glucagon by laypeople, the authors say.

If subsequent studies hold up and the intranasal product is approved by regulatory bodies, it could ultimately replace intramuscular glucagon, study coauthor Jennifer Sherr, MD, PhD, assistant professor of pediatrics (endocrinology) at Yale University School of Medicine, New Haven, Connecticut, told Medscape Medical News.

"As intranasal glucagon is passively absorbed through the nasal mucosa and no cooperation or inhalation is required from the patient, I do not see a situation where this therapy wouldn't be ideal," she said.

"Given the ease of administration and efficacy demonstrated in the present study, intranasal glucagon appears well poised to eventually replace the currently commercially available injected formulations," she added.

Both Products Rapidly Normalized Blood Glucose

The study was conducted at eight clinics that are part of the US T1D Exchange clinic network. The 75 participants were men and women aged 18 to 64 years with type 1 diabetes of at least 2 years' duration. They were randomized to 3 mg of intranasal glucagon or 1 mg of intramuscular glucagon (GlucaGen HypoKit, Novo Nordisk) during the first visit and to the other glucagon product during the second visit, a median of 16 days later.

After an overnight fast and with starting glucose levels of at least 90 mg/dL, patients were given intravenous insulin infusions until plasma glucose levels dropped below 60 mg/dL (mean, 55 mg/dL in both groups). The insulin infusion was then stopped and one of the two glucagon products given 5 minutes later.

The intranasal glucagon was administered by an investigator by placing the device's tip into one of the patient's nostrils and depressing a plunger connected to a piston that discharges the powder. The product is absorbed through the nasal mucosa, with no inhalation or any other cooperative action required by the patient.

(An earlier phase 1 study had shown that glucagon absorption and pharmacokinetics are not disrupted by nasal congestion.)

Treatment success was defined as an increase in plasma glucose to 70 mg/dL or greater or an increase of at least 20 mg/dL from the glucose nadir within 30 minutes of glucagon receipt, without additional actions needed. These criteria were met on 74 of the 75 intranasal (98.7%) and all 75 (100%) intramuscular dosing instances.

The one unsuccessful intranasal dosing came close though, reaching 65 mg/dL by 30 minutes and 72 mg/dL by 40 minutes (from a nadir of 47 mg/dL).

The rise in glucose concentrations after intranasal glucagon lagged behind the rise after intramuscular glucagon by about 5 minutes (P < .001).

However, glucagon levels had reached pharmacological levels indicating rapid absorption via both routes within 5 minutes of administration, Dr Rickels and colleagues stress.

The mean time to reach 70 mg/dL or a 20-mg/dL increase was 16 minutes with intranasal vs 13 minutes with intramuscular glucagon (P < .001).

Adverse events included transient head or facial discomfort in 25% of patients with intranasal vs 9% with intramuscular dosing, vomiting in 17% vs 12%, and nausea without vomiting in an additional 18% vs 26%, respectively (P = .59).

Potential Uses of Intranasal Glucagon

Previous studies have demonstrated successful use of intranasal glucagon in children with type 1 diabetes and in adults when administered by trained laypeople.

Dr Sherr pointed out that although restraint may be required to administer intranasal insulin to a person who is combative because of severe hypoglycemia, that's also the case with injected glucagon.

And she told Medscape Medical News that the intranasal product could also be potentially useful for people with type 2 diabetes treated with insulin or sulfonylureas.

"Knowing first-hand how difficult it is to treat severe hypoglycemia with an intramuscular injection of glucagon that needs to be reconstituted while a loved one is having a severe hypoglycemic reaction, I'm looking forward to the day when this new way to give glucagon is available to us all."

The study was funded by a grant from the Leona M and Harry B Helmsley Charitable Trust, National Center for Research Resources, National Center for Advancing Translational Sciences, National Institutes of Health, and Locemia Solutions. Dr Rickels has received consultancy payments from Longevity Biotech, Janssen Research & Development, and Semma Therapeutics and research support from Merck. Dr Sherr's nonprofit employer has received grants for support of supplies for investigator-initiated studies from Medtronic. Disclosures for the coauthors are listed in the article.

Diabetes Care. December 17, 2015. Abstract

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