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Could Glucagon-like Peptide-1 (GLP-1) Agonists Be Delivered Intranasally?

Apr 4, 2014

Possibility of non-subcutaneous administration could increase patient compliance…. 

GLP-1 agonists are effective therapeutic options for treating diabetes. While their effectiveness has been established, compliance with these medications may be limited in some patients due to their subcutaneous route of administration and gastrointestinal adverse effects.

In a recent prospective, double-blind, placebo-controlled trial, researchers assessed the efficacy and safety of GLP-1 administered in nasal dosage form.

In this exploratory study, a total of 26 type 2 diabetic patients, between the ages of 20 and 70, were assessed. At the time of inclusion, these patients were inadequately controlled and using a stable regimen of oral anti-diabetic medications. Researchers excluded patients considered as having severe micro- and macrovascular complications, frequent hypoglycemic episodes, nasal cavity abnormalities, asthma and severe renal and hepatic dysfunction.

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Study participants were randomly assigned to receive the GLP-1 or placebo – with the GLP-1 group containing 18 patients and the placebo group having 8 patients. The intranasal GLP-1 preparation contained 1.2 mg of human GLP-1 amide, provided in a capsule containing 1.2 mg of recombinant human GLP-1 (7–36) amide. This was administered immediately before meals, for duration of 2 weeks, using a special nasal device.

Before each meal, on days 0, 7 and 14, researchers collected data using blood samples, medical examination and a 100-mm visual analog scale to measure hunger sensation. Plasma glucagon levels were measured radioimmunoassay, plasma active levels of GLP-1 via blood sample tubes containing dipeptidyl peptidase-4 (DPP-4) with an ELISA kit. Data was presented as means and standard deviations and variables at single time points or as area under the curve (AUC) were analyzed using t-tests along with ANOVA for repeated measures.

Of the study participants, oral diabetic agents were similar between members of each group.

Five minutes after administering the nasal preparation, plasma active GLP-1 levels increased to 47.2 pmol/L, with the Tmax of GLP-1 being reached at 8.1 minutes. Levels of plasma active GLP-1, 5 to 30 minutes post-administration and AUC at 180 minutes were significantly higher in the GLP-1 group compared to the placebo group.

Plasma glucose levels between baseline and 30 minutes were significantly lower in the GLP-1 group compared to placebo. This was also the case with plasma glucagon levels. From baseline to 30 minutes and 180 min in the GLP-1 group were significantly lower than those in the placebo.

At Day 14, compared to Day 0, glycoalbumin levels had decreased significantly (19.4 +/- 3.3 to 18.8 +/- 3.1%; P = 0.003). As expected, these were significantly lower in the GLP-1 group than in the placebo group (19.3 +/- 2.5%; P = 0.034).

Levels of 1,5-anhydroglucitol also significantly increased at day 14 compared with day 0 (8.0 +/- 6.9 to 8.7 +/- 6.5 mg/mL; P = 0.036). These were notably higher in the GLP-1 group than in the placebo group (7.9 +/- 5.1 mg/mL; P=0.041).

In study participants, 3 patients in intranasal GLP-1 group experienced nausea and 2 experienced stomach discomfort. These adverse effects, however, were considered transient and insignificant, after disappearing within approximately 3 days.

Since GLP-1 agonists help to decrease hunger in body weight, it was expected that study participants using intranasal GLP-1 would have experienced some of these benefits – this, however, was not the case. Among study participants, total body weight, food intake and hunger sensation remained virtually identical. Longer studies are necessary to assess the effect of intranasal GLP-1 on hunger and body weight.

This study showed that the use of intranasal GLP-1 not only induced early phase insulin secretion and inhibited inappropriate glucagon secretion but also improvement in intermediate-term markers of glycemic control – all without significant adverse events.

While this new route of administration for this class of medication may be a promising alternative from those who are not compliant with subcutaneous GLP-1 agonists, due to their route of administration, it may come at a hefty price. The bioavailability of this agent was very low (2.7%) which may amount to higher costs.

Practice Pearls:
  • Intranasal GLP-1 may potentially provide the same glycemic benefits as GLP-1 agonist with improved patient compliance
  • Long-term treatment needs to be evaluated in large trials to determine the safety and efficacy of nasally administered GLP-1
  • No significant adverse events were observed after intranasal GLP-1 further

Ueno H, Mizuta M, Shiiya T, et al. Exploratory Trial of Intranasal Administration of Glucagon-like Peptide-1 in Japanese Patients With Type 2 Diabetes. Diabetes Care.