There is still no oral formulation of insulin available clinically, particularly due to the low bioavailability of intact insulin via oral route delivery.1 However, encouraging findings were presented in the President’s Oral Session at the American Diabetes Association’s 77th Scientific Sessions. This trial demonstrated for the first time that it is feasible to formulate an oral basal insulin with comparable efficacy to subcutaneous insulin.2
The feasibility study enrolled 50 insulin naïve type 2 diabetes (T2DM) patients, who were inadequately controlled (HbA1c 7–10%) on metformin alone or in combination with other oral agents.2 The patients were randomized 1:1 in a double-blind, double-dummy fashion to receive an oral insulin tablet (OI338GT) or an injection of insulin glargine U100 (IGlar) once-daily for a period of eight weeks.2 To allow participants to achieve a fasting plasma glucose in the target range of 4.4-7.0mmol/L, the insulin doses were up-titrated weekly on an individualized basis aided by a pre-specified algorithm until no additional therapeutic benefit was seen.2
The formulation used in this study, a GIPET I tablet (OI338GT), is a basal, acylated insulin analog with a half-life of around 70 hours.2 The development of GIPET® (Gastrointestinal Permeation Enhancement Technology) allows the oral administration of an otherwise poorly bioavailable compound, with no toxicity of concern reported in the phase I trials.3
At 8 weeks, both oral insulin tablet and insulin glargine injection substantially improved the glycemic control to a similar extent.2
The primary endpoint of fasting plasma glucose was reduced from 9.7mmol/L at baseline to 7.2mmol/L in the OI338GT arm, whereas it was 9.1mmol/L at baseline reduced to 6.7mmol/L in the lGlar arm.2 The treatment difference produced by both treatments was not significant (5.2%, 95% CI: -8.8 to 19.1, p=0.457).2
The extent of hemoglobin A1c (HbA1c) reduction, the gold standard for glucose monitoring in patients with diabetes,4 in the OI338GT arm, was also equivalent to the lGlar arm, producing a non-significant difference of 0.3 percentage points between both arms (95% CI: -0.03 to 0.63, p=0.077).2
Similarly, alternative markers of glycemia such as fructosamine and fasting C-peptide, were also not significantly different (p=0.37 for fructosamine; p=0.68 for fasting C-peptide).2
The incidence of hypoglycemia was low in both arms, and there were no serious hypoglycemic events.2 Other adverse-event rates did not differ between the two arms, as reported by the study author, Plum-Mörschel, chief executive officer of Profil Mainz GmbH & Co. KG.5
“After almost 100 years of oral insulin research, this trial demonstrates for the first time that an oral basal insulin can safely improve the glycemic control in patients with type 2 diabetes,” Dr. Plum-Mörschel said in her presentation.5
However, the study co-author, Karsten Wassermann, project vice president of global development at Novo Nordisk A/S, cautioned. “Oral insulin has long been considered a highly desirable option in diabetes research, potentially freeing patients from continuous injections in favor of an easy-to-take tablet. While these data are highly encouraging, there is a need to optimize the tablet to further increase the insulin bioavailability.”6
Indeed, further development of this Novo Nordisk-sponsored oral insulin project has been discontinued because the bioavailability of OI338GT is low, and thus it has been assessed to not be commercially viable.5,6 Nevertheless, the improvement of technologies involved in the product’s development is the focus of ongoing research.6
“Within the scientific community, there is an ongoing search for alternative ways to administer insulin so that we can enable diabetes patients to receive insulin without continuously breaking the skin barrier with a needle. The goal is to provide optimal coverage and ease insulin therapy for patients with diabetes, and now, we’re one step closer to achieving that vision.” Karsten Wassermann concluded.6
1. Wong CY, Martinez J, Dass CR. Oral delivery of insulin for treatment of diabetes: status quo, challenges and opportunities. J Pharm Pharmacol. 2016;68(9):1093-108.
2. Plum-Morschel L, Heise T, Zijlstra, et al. Efficacy and Safety of Oral Basal Insulin: Eight-Week Feasibility Study in People with Type 2 Diabetes (T2DM). American Diabetes Association 2017 Scientific Sessions. June 13, 2017; San Diego, California. Abstract 380-OR.
3. Leonard TW Lynch J, McKenna MJ, et al. Promoting absorption of drugs in humans using medium-chain fatty acid-based solid dosage forms: GIPET. Expert Opin Drug Deliv. 2006;3(5):685-92.
4. Ribeiro RT, Macedo MP, Raposo JF. HbA1c, Fructosamine, and Glycated Albumin in the Detection of Dysglycaemic Conditions. Curr Diabetes Rev. 2016;12(1):14-9.
5. Oral Basal Insulin Shows Promise in Type 2 Diabetes. Medscape. 2017 (Accessed July 26 2017, at http://www.medscape.com/viewarticle/882211).
6. Daily, Long-Acting Oral Insulin Tablet Provides Comparable Glycemic Control to Insulin Glargine Injection in Patients with Type 2 Diabetes. PR Newswire. 2017 (Accessed July 26 2017, at http://www.prnewswire.com/news-releases/daily-long-acting-oral-insulin-tablet-provides-comparable-glycemic-control-to-insulin-glargine-injection-in-patients-with-type-2-diabetes-300473318.html).