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Efficacy and safety of oral basal insulin versus subcutaneous insulin glargine in type 2 diabetes: a randomised, double-blind, phase 2 trial

Published on Mar 1, 2019in The Lancet Diabetes & Endocrinology 24.54
· DOI :10.1016/S2213-8587(18)30372-3
Inge B. Halberg1
Estimated H-index: 1
(Novo Nordisk),
Karsten Lyby5
Estimated H-index: 5
(Novo Nordisk)
+ 3 AuthorsLeona Plum-Mörschel5
Estimated H-index: 5
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Abstract
Summary Background Oral insulin 338 (I338) is a long-acting, basal insulin analogue formulated in a tablet with the absorption-enhancer sodium caprate. We investigated the efficacy and safety of I338 versus subcutaneous insulin glargine (IGlar) in patients with type 2 diabetes. Methods This was a phase 2, 8-week, randomised, double-blind, double-dummy, active-controlled, parallel trial completed at two research institutes in Germany. Insulin-naive adult patients with type 2 diabetes, inadequately controlled on metformin monotherapy or combined with other oral antidiabetic drugs (HbA 1c 7·0–10·0%; BMI 25·0–40·0 kg/m 2 ), were randomly assigned (1:1) to receive once-daily I338 plus subcutaneous placebo (I338 group) or once-daily IGlar plus oral placebo (IGlar group). Randomisation occurred by interactive web response system stratified by baseline treatment with oral antidiabetic drugs. Patients and investigators were masked to treatment assignment. Weekly insulin dose titration aimed to achieve a self-measured fasting plasma glucose (FPG) concentration of 4·4–7·0 mmol/L. The recommended daily starting doses were 2700 nmol I338 or 10 U IGlar, and maximum allowed doses throughout the trial were 16 200 nmol I338 or 60 U IGlar. The primary endpoint was treatment difference in FPG concentration at 8 weeks for all randomly assigned patients receiving at least one dose of trial product (ie, the full analysis set). The trial has been completed and is registered at ClinicalTrials.gov, number NCT02470039. Findings Between June 1, 2015, and Oct 19, 2015, 82 patients were screened for eligibility and 50 patients were randomly assigned to the I338 group (n=25) or the IGlar group (n=25). Mean FPG concentration at baseline was 9·7 (SD 2·8) in the I338 group and 9·1 (1·7) in the IGlar group. Least square mean FPG concentration at 8 weeks was 7·1 mmol/L (95% CI 6·4–7·8) in the I338 group and 6·8 mmol/L (6·5–7·1) in the IGlar group, with no significant treatment difference (0·3 mmol/L [–0·5 to 1·1]; p=0·46). I338 and IGlar were well tolerated by patients. Adverse events were reported in 15 (60%) patients in the I338 group and 17 (68%) patients in the IGlar group. The most common adverse events were diarrhoea (three [12%] patients in each group) and nasopharyngitis (five [20%] in the I338 group and two [8%] in the IGlar group). Most adverse events were graded mild (47 of 68 events), and no severe adverse events were reported. One patient in the IGlar group had a treatment-emergent serious adverse event (urogenital haemorrhage of moderate intensity, assessed by the investigator as unlikely to be related to treatment; the patient recovered). Incidence of hypoglycaemia was low in both groups (n=7 events in the I338 group; n=11 in the IGlar group), with no severe episodes. Interpretation I338 can safely improve glycaemic control in insulin-naive patients with type 2 diabetes with no evidence of a difference compared with insulin glargine, a widely used subcutaneously administered basal insulin. Further development of this particular oral insulin project was discontinued because I338 doses were high and, therefore, production of the required quantities of I338 for wide public use was deemed not commercially viable. Improvement of technologies involved in the product's development is the focus of ongoing research. Funding Novo Nordisk.
  • References (25)
  • Citations (6)
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References25
Newest
Published on Nov 14, 2018in Science Translational Medicine 17.16
Stephen T. Buckley6
Estimated H-index: 6
(Novo Nordisk),
Tine A. Bækdal3
Estimated H-index: 3
(Novo Nordisk)
+ 19 AuthorsRikke Kaae Kirk8
Estimated H-index: 8
(Novo Nordisk)
Oral administration of therapeutic peptides is hindered by poor absorption across the gastrointestinal barrier and extensive degradation by proteolytic enzymes. Here, we investigated the absorption of orally delivered semaglutide, a glucagon-like peptide-1 analog, coformulated with the absorption enhancer sodium N -[8-(2-hydroxybenzoyl) aminocaprylate] (SNAC) in a tablet. In contrast to intestinal absorption usually seen with small molecules, clinical and preclinical dog studies revealed that ab...
10 Citations Source Cite
Published on May 1, 2018in Diabetes 7.20
Mary Courtney Moore25
Estimated H-index: 25
,
Erica Nishimura15
Estimated H-index: 15
+ 11 AuthorsL. Merkle Moore1
Estimated H-index: 1
Oral insulin avoids the need for injections, and insulin enters via the hepatic portal vein (Po), the normal route of secretion. We examined the effect of I338, an acylated analog designed for oral use, dosed either Po to match the oral absorption profile or IV to match the steady state basal subcutaneous (SC) plasma profile, on a Po glucose challenge. To achieve steady-state concentrations in normal dogs, I338 was infused IV 45 min daily for 4 days. On day 5 a primed, continuous infusion of 3- ...
1 Citations Source Cite
Published on Nov 1, 2016in Advanced Drug Delivery Reviews 15.52
Tanira A.S. Aguirre5
Estimated H-index: 5
(UCS: University of Caxias do Sul),
Desirée Teijeiro-Osorio6
Estimated H-index: 6
(University of Santiago de Compostela)
+ 3 AuthorsDavid J. Brayden35
Estimated H-index: 35
(UCD: University College Dublin)
The development of oral dosage forms that allows absorption of therapeutic peptides to the systemic circulation is one of the greatest challenges for the pharmaceutical industry. Currently, a number of technologies including either mixtures of penetration enhancers or protease inhibitors and/or nanotechnology-based products are under clinical development. Typically, these formulations are presented in the form of enteric-coated tablets or capsules. Systems undergoing preclinical investigation in...
82 Citations Source Cite
Published on Feb 1, 2016in Journal of Endocrinological Investigation
Vajihe Akbari8
Estimated H-index: 8
(IUMS: Isfahan University of Medical Sciences),
Fatemeh Hendijani5
Estimated H-index: 5
(IUMS: Isfahan University of Medical Sciences)
+ 4 AuthorsS.A. Mostafavi2
Estimated H-index: 2
(IUMS: Isfahan University of Medical Sciences)
Introduction A systematic review and meta-analysis of interventional studies was conducted to compare the efficacy and safety of oral insulin versus subcutaneous (SC) insulin in diabetic patients.
6 Citations Source Cite
Published on Aug 1, 2015in Diabetes, Obesity and Metabolism 6.13
Julio Rosenstock26
Estimated H-index: 26
,
P. Hollander6
Estimated H-index: 6
(Baylor University)
+ 5 AuthorsMelvin J. Prince15
Estimated H-index: 15
(Eli Lilly and Company)
Aims To compare the efficacy and safety of LY2963016 insulin glargine (LY IGlar) and the reference product (Lantus®) insulin glargine (IGlar) in combination with oral antihyperglycaemic medications in patients with type 2 diabetes (T2D). Methods This phase III, randomized, double-blind, 24-week study enrolled patients with T2D who were insulin-naive [glycated haemoglobin (HbA1c) ≥7 and ≤11.0%] or previously on IGlar (HbA1c ≤11%) and treated with ≥2 oral antihyperglycaemic medications. Patients w...
49 Citations Source Cite
Published on Aug 1, 2015in Therapeutic Delivery
Marlene Lopes6
Estimated H-index: 6
,
Susana Simões10
Estimated H-index: 10
+ 2 AuthorsAntónio Sousa Ribeiro8
Estimated H-index: 8
Oral insulin able to induce an efficient antihyperglycemic effect either to replace or complement diabetes mellitus therapy is the major goal of health providers, governments and diabetic patients. Oral therapy is associated not only with the desire to exclude needles from the daily routine of diabetic patient but also with the physiological provision of insulin they would get. Despite numerous efforts over the past few decades to develop insulin delivery systems, there is still no commercially ...
10 Citations Source Cite
Eric Zijlstra10
Estimated H-index: 10
,
Lutz Heinemann52
Estimated H-index: 52
,
Leona Plum-Mörschel1
Estimated H-index: 1
Optimal coverage of insulin needs is the paramount aim of insulin replacement therapy in patients with diabetes mellitus. To apply insulin without breaking the skin barrier by a needle and/or to allow a more physiological provision of insulin are the main reasons triggering the continuous search for alternative routes of insulin administration. Despite numerous attempts over the past 9 decades to develop an insulin pill, no insulin for oral dosing is commercially available. By way of a structure...
29 Citations Source Cite
Published on Sep 1, 2013in Diabetes Technology & Therapeutics 4.49
David Raymond Owens51
Estimated H-index: 51
Abstract The natural history of type 2 diabetes mellitus (T2DM) is a relentless progression of β-cell failure and dysregulation of β-cell function with increasing metabolic derangement. Insulin remains the only glucose-lowering therapy that is efficacious throughout this continuum. However, the timing of introduction and the choice of insulin therapy remain contentious because of the heterogeneity of T2DM and the well-recognized behavioral and therapeutic challenges associated with this mode of ...
33 Citations Source Cite
Published on Aug 1, 2013in Diabetes, Obesity and Metabolism 6.13
Jiten Vora35
Estimated H-index: 35
(University of Liverpool),
T. Heise1
Estimated H-index: 1
Lowering blood glucose with insulin therapy towards beneficial target levels while also avoiding hypoglycaemia is a challenging task. An important confounding factor, which might be under-appreciated in this scenario, is that of variable glucose readings causing difficulties with dose adjustment. Furthermore, this glucose variability is, to some extent, a reflection of variability in the glucose-lowering action of the insulin therapy itself. Not only is glucose variability a major confounding fa...
34 Citations Source Cite
Published on Aug 1, 2013in Diabetes, Obesity and Metabolism 6.13
Luigi Meneghini26
Estimated H-index: 26
(UM: University of Miami),
J. Kesavadev1
Estimated H-index: 1
+ 2 AuthorsPriscilla Hollander17
Estimated H-index: 17
(Baylor University Medical Center)
Aims This study assessed the efficacy and safety of once-daily insulin initiation using insulin detemir (detemir) or insulin glargine (glargine) added to existing metformin in type 2 diabetes (T2D). Methods This 26-week, multinational, randomized, treat-to-target trial involved 457 insulin-naive adults with T2D (HbA1c 7–9%). Detemir or glargine was added to current metformin therapy [any second oral antidiabetic drug (OAD) discontinued] and titrated to a target fasting plasma glucose (FPG) ≤90 m...
40 Citations Source Cite
Cited By6
Newest
Published on May 16, 2019in Clinical Pharmacokinectics 4.68
Inge B. Halberg1
Estimated H-index: 1
,
Karsten Lyby5
Estimated H-index: 5
+ 3 AuthorsEric Zijlstra10
Estimated H-index: 10
Source Cite
Published on Apr 16, 2019in JAMA 51.27
B HirschIrl63
Estimated H-index: 63
(UW: University of Washington)
Source Cite
Published on Apr 1, 2019in Journal of Pharmaceutical Sciences 3.20
Alex Abramson2
Estimated H-index: 2
(MIT: Massachusetts Institute of Technology),
Florencia Halperin13
Estimated H-index: 13
(Brigham and Women's Hospital)
+ 1 AuthorsGiovanni Traverso23
Estimated H-index: 23
(MIT: Massachusetts Institute of Technology)
Abstract Oral semaglutide, which has undergone multiple phase 3 clinical trials, represents the first oral biologic medication for type 2 diabetes in the form of a daily capsule. It provides similar efficacy compared with its weekly injection counterpart, but it demands a dose on the order of 100 times as high and requires more frequent administration. We perform a cost effectiveness analysis using a first and second order Monte Carlo simulation to estimate quality-adjusted life expectancies ass...
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Published on Apr 1, 2019in Nature Reviews Endocrinology 24.65
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Published on Feb 13, 2019in Pharmaceutics
Caroline Twarog1
Estimated H-index: 1
,
Sarinj Fattah3
Estimated H-index: 3
+ 3 AuthorsDavid J. Brayden35
Estimated H-index: 35
Salcaprozate sodium (SNAC) and sodium caprate (C10) are two of the most advanced intestinal permeation enhancers (PEs) that have been tested in clinical trials for oral delivery of macromolecules. Their effects on intestinal epithelia were studied for over 30 years, yet there is still debate over their mechanisms of action. C10 acts via openings of epithelial tight junctions and/or membrane perturbation, while for decades SNAC was thought to increase passive transcellular permeation across small...
1 Citations Source Cite