Gens X, Y and diabetes: Not as invincible as they think?

An experimental glucagonlike peptide-1 (GLP-1) agonist, administered intranasally before meals, improves postmeal markers of glycemic control without severe adverse events in patients with type 2 diabetes, an exploratory trial finds.

Currently available agonists of GLP-1 are effective in treating type 2 diabetes but must be injected subcutaneously and can cause gastrointestinal adverse events. This experimental product, comprising a powder formulation of recombinant human GLP-1 (Asubio Pharma, Kobe, Japan) and a special intranasal injector device (SPG Technology, Miyazaki, Japan), might offer an alternative.

"Long-term treatment with this new nasal GLP-1 should be evaluated in larger trials to determine its safety, efficacy, and acceptability as a novel treatment for type 2 diabetes," say the authors, Hiroaki Ueno, MD, from the University of Miyazaki, Japan, and colleagues. Their results were published online March 25 in Diabetes Care.

Incretin expert Daniel J. Drucker, MD, from the Lunenfeld Tanenbaum Research Institute at Mt. Sinai Hospital, Toronto, Ontario, told Medscape Medical News, "If folks could deliver a stable degradation-resistant GLP-1 analog using this approach that would not have to be injected and would have an excellent tolerability profile and reasonable bioavailability, this would be very exciting."

However, Dr. Drucker cautioned that while the new findings are "innovative and proof of concept….Much more work needs to be done."

Glycemic Control Markers Improved

The study enrolled 26 adult type 2 diabetes patients who were inadequately controlled using oral glucose-lowering drugs. Mean HbA1c was 7.7% for the 18 who were randomized to the GLP-1 compound and 7.5% for 8 patients randomized to intranasal placebo (P = .74).

Patients sprayed the GLP-1 or placebo into their nasal cavities before test meals for 2 weeks. Plasma active GLP-1 levels increased following the nasal spray of GLP-1, reaching a maximum plasma level at about 8 minutes before declining, and were significantly higher than placebo at 5 to 30 minutes after administration. Serum insulin levels were significantly higher than with placebo at 15 minutes.

The fact that this is a recombinant form of "native" GLP-1 is the reason for the rapid peripheral appearance and disappearance of active GLP-1 in diabetic patients following administration of the active compound, the researchers explain.

Postmeal rises in plasma glucose and plasma glucagon from baseline to 30 minutes were significantly lower in the GLP-1 group, and the group difference for increase in plasma glucagon was also significant at 180 minutes (all P < .05 vs placebo).

At day 14, glycoalbumin levels significantly dropped from baseline only in the GLP-1 group (19.4% to 18.8%, P = .003) and were significantly lower with GLP-1 compared with placebo (P = .034).

And levels of 1,5 anhydroglucitol, a marker of short-term glycemic control, were significantly increased at day 14 compared with baseline only in the GLP-1 group (8.0 to 8.7 mg/mL, P = .036).

There were no differences between the 2 groups in body weight, total food intake, or hunger sensation as assessed with the visual analog scale before each meal.

No major adverse events occurred with intranasal GLP-1, and no patients withdrew from the study. Nausea occurred in 3 patients and discomfort in 2, but these symptoms disappeared within 3 days. None vomited.

The GLP-1 product "induced early-phase insulin secretion, inhibition of inappropriate glucagon secretion, and improvement in intermediate-term markers of glycemic control without severe adverse events," the researchers say.

Worthwhile Trade-offs?

Both the authors and Dr. Drucker note the possible pros and cons of this product. It's easier to administer and less painful than subcutaneous injections, which are major reasons that "patients refuse to use GLP-1 analog drugs," say Dr. Ueno and colleagues.

And nausea and vomiting were less common with this product than with existing GLP-1 agonists such as exenatide (Byetta, Amylin/Lilly) and liraglutide (Victoza, Novo Nordisk).

But adherence might be reduced, since it would have to be given before each meal. "Native GLP-1 has a short half-life, so it has to be administered very frequently," Dr. Drucker explained.

And lower bioavailability (just 2.7% compared with intravenous GLP-1 administration) could translate to higher costs.

The authors point out that intranasally administered GLP-1 could possibly be combined with an oral dipeptidyl peptidase (DPP)-4 inhibitor to reduce the amount of GLP-1 required.

The study was supported by the Practical Application for the Japan Science and Technology Agency. Asubio Pharma provided the drug and helped in conducting the trial. The authors report no other potential conflicts of interest. Dr. Drucker has served within the past 12 months as an advisor to or consultant for Arisaph Pharmaceuticals, Diartis Pharmaceuticals, Intarcia Therapeutics, Merck Research Laboratories, Novo Nordisk, NPS Pharmaceuticals, Receptos, Sanofi, Takeda, and Transition Pharmaceuticals. Neither Dr. Drucker nor his family members hold stock directly or indirectly in any of these companies.

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