Insulin in Capsule - Safety and Efficacy Study in Patients with Early-Stage Type 2 Diabetes

Insulin in Capsule - Safety and Efficacy Study in Patients with Early-Stage Type 2 Diabetes
Kwon Park, PharmD
CentraCare - St. Cloud

Background: The most common method of administering insulin to people with diabetes is through injections. Insulin is also available as an inhaled formulation but is not used widely in practice. Despite its efficacy, insulin is generally considered as one of the last pharmacotherapy options due to the risk of hypoglycemia and weight gain. New et al. explains the oral formulation can deliver insulin directly to the liver and avoid peripheral hyperinsulinemia. The author describes this delivery method as the major advantage over injectable insulin as one can avoid hypoglycemia and weight gain. Insulin is a poly-peptide protein that is normally broken down by digestive enzymes and loses its physiological ability when ingested orally. However, a novel delivery technology called Axcess™ developed by Diabetology Ltd increases the absorption of peptides across the intestinal wall without any chemical modification of the active compounds and thereby maintaining its physiological effect. Capsulin™ is a novel drug in the capsule form that contains regular human insulin in the form of dry white powder with excipients such as natural bile salt and an antioxidant to prevent degradation in the gut, to penetrate the mucin layer, and to aid its uptake by and across intestinal cells.

Purpose: The primary objective of this study was to evaluate the safety and efficacy of Capsulin™, an oral insulin capsule formulation, in patients with uncontrolled type 2 diabetes treated with metformin.

Study Design: This was a phase 2b open-label, randomized, comparative study that was conducted at 15 centers across India. The study included male or female patients aged 35-60 years old with type 2 diabetes diagnosed less than two years prior to enrollment with HbA1c of 7-9.5%, with body mass index (BMI) = 18-30 kg/m2 at baseline, treated with metformin (1000 to 2500 mg per day), and on regular diet and exercise regimen at least 12 weeks prior to enrollment. The study excluded patients who received treatment with insulin or any other oral diabetic medications besides metformin within three months prior to enrollment. The participants were randomized into three groups in a 1:1:1 ratio: Capsulin™ 75 IU (2.5 mg) twice daily (BID), 150 IU (5 mg) BID, and 300 IU (10 mg) BID for 12 weeks. The participants in the 150 IU BID and 300 IU BID groups underwent a run-in period of one week with each previous lower dose before receiving the assigned dose. After the run-in period, participants received the same dose without titration during the entire study period. Adherence was assessed through the patient diary and on the basis of the number of capsules dispensed versus the number of capsules used and returned in the capsule strips. The primary endpoint of this study was the change in HbA1c level after 12 weeks from baseline. The secondary endpoints were change in fasting blood glucose, 2-hour postprandial glucose, adverse events, total cholesterol, triglycerides, and low-density lipoprotein (LDL) cholesterol.

Results: The study was conducted from January 2019 to July 2020, and it was originally intended to include 195 participants. However, the trial was terminated early with 132 participants because of logistical difficulties with recruiting patients during the COVID-19 pandemic. Of these, 32 participants were excluded from the analysis because they were unable to attend the central clinic mainly due to lockdown from the COVID-19 pandemic. Thus, 100 patients were included in the analysis: 75 IU BID group (n=33), 150 IU BID group (n=29), and 300 IU BID group (n=38). The 150 IU BID and 300 IU BID groups met the primary endpoint with mean change in HbA1c of -0.52% (P=0.004) and -0.42% (P=0.009), respectively. The 75 IU BID group had a mean change in HbA1c of -0.11% but did not reach statistical difference (P=0.522). For the secondary endpoint of change in fasting blood glucose, only the 150 IU BID group reached a statistical difference of -18.8 mg/dl (P=0.017). Although all groups showed a reduction in 2-hour postprandial glucose ranging 17 to 31 mg/dl, they were not statistically significant. No hypoglycemia, gastrointestinal side effects, or significant weight gain were observed throughout the 12 weeks of the study. Mean reduction of total cholesterol, LDL, and triglycerides were -15 mg/dl, -9.9 mg/dl, and -40 mg/dl, respectively in 150 IU BID group. The results from other groups were not reported. The average adherence was calculated as 97%. In addition, a sub-group analysis suggested the potential of the 150 IU BID group to lower HbA1c levels by as much as 1.58% in patients with starting values of 9-9.5%.

Conclusions: ‌Capsulin™ 150 IU administered orally twice daily reduces HbA1c by 0.52% and fasting blood glucose level by 18.8 mg/dl over a 12-week period without causing significant weight gain or hypoglycemia. One limitation of the study is the absence of a placebo-controlled group to limit the potential bias of metformin on the results.

Key Point: This study shows a promising future of orally administered insulin for the treatment of type 2 diabetes by improving HbA1c without causing hypoglycemia or weight gain. However, it is unclear if the HbA1c lowering effect of Capsulin™ is affected by dose or baseline HbA1c as the study results showed no difference between the 150 IU and 300 IU groups but showed a much greater HbA1c reduction in patients with higher HbA1c baseline levels. The author explained orally administered insulin works directly on the liver where the level of glucose control is determined by the level of glucose itself rather than dose of insulin. Therefore, Capsulin™ works in a glucose-dependent manner without hypoglycemia risk and causes greater A1c reduction in patients with higher glucose level at baseline. More studies will be needed to test this hypothesis.


  1. New RRC, Ramanujam S, Chaudhari V, Bogus M, Travers GN, Namjoshi G. Safety and efficacy of an oral insulin (Capsulin) in patients with early-stage type 2 diabetes: A dose-ranging phase 2b study. Diabetes Obes Metab. 2022;18. doi:10.1111/dom.14922
  2. Diabetology Ltd - Home.