World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease
World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease
December 16, 2019
5 min read

Noninjectable options to deliver insulin, manage diabetes

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George Grunberger

LOS ANGELES — Several cutting-edge advances in noninjectable insulin delivery methods could offer new ways for people with diabetes to manage the disease and better control glucose response, with the possibility of an oral insulin formulation closer than ever before to becoming reality, according to a speaker at the World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease.

Oral delivery is the simplest and least invasive way to deliver many pharmaceuticals, but many, including insulin, cannot survive passage through the stomach or the gastrointestinal (GI) tract, George Grunberger, MD, FACP, FACE, chairman of the Grunberger Diabetes Institute in Bloomfield Hills, Michigan, said during a presentation.

“Mother nature does not want your GI tract to absorb large molecules,” Grunberger said. “There are lots of things out there that serve as barriers to oral injections of peptides and proteins. These obstacles are built in to protect us ... to make sure nothing gets through that does not belong in the GI tract. For decades, people have tried to come up with other ways to deal with that, and there are some fascinating approaches [that] are trying to remove or decrease those barriers.”

Oral insulin

Inspired by the leopard tortoise’s ability to passively reorient, NIH-funded researchers developed an ingestible, self-orienting, millimeter-scale applicator, or SOMA, that autonomously positions itself to engage with GI tissue and inject insulin, Grunberger said. In an article published in February in Science, the researchers wrote that the oral capsule deploys milliposts fabricated from active pharmaceutical ingredients directly through the gastric mucosa while avoiding perforation. In vivo studies conducted in rats and swine support the applicator’s safety and, using insulin as a model drug, demonstrated that the SOMA device delivers active pharmaceutical ingredient plasma levels comparable to those achieved with subcutaneous millipost administration, the researchers wrote.

Insulin words 2019 
Several cutting-edge advances in noninjectable insulin delivery methods could offer new ways for people with diabetes to manage the disease and better control glucose response, with the possibility of an oral insulin formulation closer than ever before to becoming reality.
Source: Adobe Stock

“You have this capsule, and inside there is a spring-loaded needle, and on it is compressed, freeze-dried insulin,” Grunberger said. “When you swallow it, it lands the right way and the needle ends up on the gastric mucosa, and then insulin gets injected into the body and the outer covering is dissolved. We’ll see where this device winds up.”

In November, Oramed Pharmaceuticals reported safety and efficacy results from its phase 2b trial of an oral formulation of human insulin. The positive top-line results from the trial, which enrolled 269 adults with type 2 diabetes, demonstrated safety and efficacy for ORMD-0801, the company’s lead oral insulin candidate, as well as a clinically meaningful reduction in HbA1c when compared with placebo. The drug has the potential to be the first commercial oral insulin capsule for the treatment of diabetes.


“It works, at least if you judge the top-line results,” Grunberger said. “They claim that, compared with placebo, the oral insulin capsule lowered HbA1c by a clinically meaningful 0.6%. This is one of the efforts, and we will see if it winds up in the clinic.”

Novo Nordisk also reported results earlier this year from a phase 2, 8-week randomized, double-blind, double-dummy controlled trial with oral insulin 338 (I338), a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate, Grunberger said. In a study published in March in The Lancet Diabetes & Endocrinology, researchers reported that I338 safely improved glycemic response for 25 insulin-naive adults with type 2 diabetes, with no evidence of a difference when compared with subcutaneously administered insulin glargine.

Further development was discontinued because I338 doses were high and production of the required quantities of I338 was deemed not commercially viable, Grunberger said.

“Fasting plasma glucose was lowered, both by injectable glargine, but also by the oral insulin, and there was no significant treatment difference,” Grunberger said. “But the company said it is too expensive.”

Inhaled insulin

An inhaled rapid-acting mealtime insulin (Afrezza, MannKind), approved by the FDA in 2015 to improve glycemic response in people with type 1 and type 2 diabetes, is known for its ability to address postprandial hyperglycemia, Grunberger said. The development comes after the first FDA-approved powdered native human insulin (Exubera, Pfizer) was withdrawn from the market in 2007.

“MannKind uses the technosphere technology to deliver insulin directly into the lungs,” Grunberger said. “The idea here is a more patient-friendly device. When you get insulin into the lungs, there is a one-cell layer between the air sac and the circulation, so it works very quickly. The idea is you can reduce fear of any postprandial hyperglycemia.”

Oral-lyn, a buccal insulin spray (Generex), also remains in development, Grunberger said. In 2015, the University of Toronto’s Center for Molecular Design and Preformulations enhanced the Oral-lyn formulation to make it more attractive for patients and prospective commercialization partners, he said. Changes included an increase in the bioavailability of insulin in the product and a reduction in the number of sprays required to achieve effective prandial glucose control.

This year, the NuGenerex Diabetes Research Center accelerated development of the reformulated Oral-lyn-2 for type 2 diabetes and Altsulin for the treatment of type 1 diabetes, Grunberger said, adding that programs are expected to begin in the first quarter of 2020.


GLP-1 receptor agonists

In September, the FDA approved oral semaglutide (Rybelsus, Novo Nordisk), the first noninjectable GLP-1 receptor agonist for the treatment of type 2 diabetes. The approval follows several large trials that demonstrated the therapy was associated with superior HbA1c reductions vs. placebo (PIONEER 4) vs. the oral SGLT2 inhibitor empagliflozin (PIONEER 2; Jardiance, Boehringer Ingelheim) and vs. the oral DPP-IV inhibitor sitagliptin (PIONEER 3; Januvia, Merck), Grunberger said. Oral semaglutide also provided significant weight loss at 52 weeks for participants with type 2 diabetes uncontrolled with metformin therapy.

Given the uniformly positive findings from phase 3 trials, which all showed dose-dependent declines in HbA1c for people with type 2 diabetes who received the drug, the approval did not come as a surprise, Grunberger said. The oral formulation uses salcaprozate sodium, or SNAC, an intestinal permeation enhancer, to facilitate a local increase in pH leading to higher solubility of the drug, Grunberger said. SNAC also interacts with cell membrane facilitating absorption within 30 minutes, he said.

“This is potentially a game changer,” Grunberger said. “It turns out that you can deliver a clinically effective peptide this way. The trick is it’s bound to SNAC, which interacts with the gastric mucosa.

“The question I ask is, do we still have to inject to manage diabetes mellitus? My answer is, not necessarily,” Grunberger said. “As far as the future of insulin delivery, we just don’t know yet. We don’t know what is going to make it to market.” – by Regina Schaffer


Grunberger G. Do we still have to inject to manage diabetes? Presented at: World Congress on Insulin Resistance, Diabetes and Cardiovascular Disease; Dec. 4-7, 2019; Los Angeles.

Abramson A, et al. Science. 2019;doi:10.1126/science.aau2277.

Halberg IB, et al. Lancet Diabetes Endocrinol. 2019;doi:10.1016/s2213-8587(18)30372.3.

Disclosure: Grunberger reports no relevant financial disclosures.