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 19.31
· 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
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.
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  • Citations (3)
Published on Aug 1, 2015in Therapeutic Delivery
Marlene Lopes6
Estimated H-index: 6
Susana Simões11
Estimated H-index: 11
+ 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
Published on Dec 1, 2012in Diabetes Care 13.40
Julio Rosenstock115
Estimated H-index: 115
(University of Toronto),
Athena Philis-Tsimikas20
Estimated H-index: 20
(Scripps Health)
+ 5 AuthorsChantal Mathieu77
Estimated H-index: 77
(Katholieke Universiteit Leuven)
OBJECTIVE To compare ultra–long acting insulin degludec with glargine for efficacy and safety in insulin-naive patients with type 2 diabetes inadequately controlled with oral antidiabetic drugs (OADs). RESEARCH DESIGN AND METHODS In this 1-year, parallel-group, randomized, open-label, treat-to-target trial, adults with type 2 diabetes with A1C of 7−10% taking OADs were randomized 3:1 to receive once daily degludec or glargine, both with metformin. Insulin was titrated to achieve prebreakfast pla...
187 Citations Source Cite
Published on Apr 1, 2003in Nature Reviews Drug Discovery 50.17
Michael Goldberg1
Estimated H-index: 1
Isabel Gomez-Orellana2
Estimated H-index: 2
The rapid integration of new technologies by the pharmaceutical industry has resulted in numerous breakthroughs in the discovery, development and manufacturing of pharmaceutical products. In particular, the commercial-scale production of high-purity recombinant proteins has resulted in important additions to treatment options for many large therapeutic areas. In addition to proteins, other macromolecules, such as the animal-derived mucopolysacharide heparins, have also seen dramatic growth as in...
291 Citations Source Cite
Published on Dec 1, 2011in Therapeutic Delivery
Edwin G. Walsh6
Estimated H-index: 6
Adamczyk Be1
Estimated H-index: 1
+ 5 AuthorsDavid J. Brayden34
Estimated H-index: 34
Oral delivery of macromolecular drugs, particularly peptides and proteins, is the focus of many academic and industrial laboratories. Armed with an increased understanding of the structure and regulation of intestinal epithelial junctional complexes of the paracellular barrier, the development of permeation enhancement technology initially focused on the specific and reversible opening of tight junctions in order to enable oral delivery. Despite intense research, none of these specific tight jun...
35 Citations Source Cite
Published on Jun 1, 2007in Diabetes Technology & Therapeutics 2.92
S. Edwin Fineberg20
Estimated H-index: 20
Thomas T. Kawabata16
Estimated H-index: 16
+ 1 AuthorsNaomi S. Fineberg55
Estimated H-index: 55
Background and Methods: Delivery of insulin to the deep lung presents unique challenges to the body's mucosal defense system. Pulmonary mucosal defense has the ability to discriminate between self and non-self antigens and has the potential for induction of immunologic tolerance. Published data concerning the immunogenicity of inhaled human insulin in drug trials will be reviewed, and data regarding the possible adverse effects of anti-insulin antibody development will be presented. Examination ...
14 Citations Source Cite
Published on Aug 1, 2004in Diabetes Technology & Therapeutics 2.92
Ehud Arbit1
Estimated H-index: 1
Insulin remains the most effective and durable drug in the armamentarium for the treatment of advanced-stage diabetes. Nevertheless, clinical studies have shown that even on insulin treatment, a significant percentage of patients fail to attain lasting glycemic control. Well-recognized reasons for this failure include issues related to patients' noncompliance with an injectable drug and the late stage at which insulin is prescribed, but less explicit reasons related to the nonphysiological way i...
69 Citations Source Cite
Published on Mar 1, 2010in Diabetes, Obesity and Metabolism 5.98
Harish Iyer9
Estimated H-index: 9
Anand Khedkar7
Estimated H-index: 7
Manish Verma1
Estimated H-index: 1
Oral insulin is one of the most exciting areas of development in the treatment of diabetes because of its potential benefit in patient convenience, rapid insulinization of liver, adequate insulin delivery avoiding peripheral hyperinsulinaemia while potentially avoiding adverse effects of weight gain and hypoglycaemia. Growing evidence that earlier initiation of intensive insulin therapy produces sustained tight glycaemic control resulting in substantial delay in complications makes an effective ...
79 Citations Source Cite
Published on Sep 1, 2013in Diabetes Technology & Therapeutics 2.92
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 ...
32 Citations Source Cite
Published on Aug 1, 2013in Diabetes, Obesity and Metabolism 5.98
Luigi Meneghini25
Estimated H-index: 25
(University of Miami),
J. Kesavadev1
Estimated H-index: 1
+ 2 AuthorsPriscilla Hollander16
Estimated H-index: 16
(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
Published on Aug 1, 2013in Diabetes, Obesity and Metabolism 5.98
Jiten Vora34
Estimated H-index: 34
(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
Cited By3
Published on Apr 1, 2019in Nature Reviews Endocrinology 20.27
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Published on Feb 13, 2019in Pharmaceutics
Caroline Twarog , Sarinj Fattah + 3 AuthorsDavid J. Brayden34
Estimated H-index: 34
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...
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Published on Mar 23, 2019in JAMA 47.66
B HirschIrl62
Estimated H-index: 62
(University of Washington)
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