New insulins and insulin therapy

Clinical Medicine & Research, 2008

Despi te 85 years of research since Banting and Best's isolation of insulin-containing extracts, 1 diabetes still remains one of the most significant causes of morbidity and mortality in the world, and its global impact is likely to accelerate over the coming decades. 2,3 Much of the medical and economic consequences of diabetes are attributable to its associated microvascular and macrovascular complications. 4-6 Two classic large-scale clinical studies, the Diabetes Control and Complications Trial (DCCT) 6 and the UK Prospective Diabetes Study (UKPDS), 7 demonstrated that intensive blood-glucose control policies can decrease the frequency of complications, arguing that physicians and patients should strive to mimic, as closely as possible, the serum levels of insulin produced by a healthy person. Secretion of insulin by the pancreas, however, is under complex regulation that depends on the intake of nutrients, other gastrointestinal peptides (e.g., incretins), and overall metabolic levels (i.e., exercise versus rest). 8 These physiological variables, which pose real challenges to the accurate metabolic replacement of insulin, are further complicated by the fact that diabetes requires self-management and therefore depends on the psychology, motivation, and understanding of the patient.

Diabetes Technology & Therapeutics, 2016

adjunct therapy with sodium-glucose cotransporter 2 inhibitors in patients with type 1 diabetes have become available and regulatory submissions are on the way, with decisions expected early next year. These drugs have the potential of addressing common side effects of insulin therapy such as glycemic variability, weight gain, or hypoglycemia. This must be balanced against notable untoward effects such as increased risk for genital mycotic infections or diabetic ketoacidosis. Mealtime insulin should ideally be absorbed very quickly after injection to counteract the rise in blood glucose with food consumption. Regarding the next-generation mealtime insulin Fiasp (NovoNordisk), it is now available in several markets and more data from the clinical Onset trial program with FiAsp were published or presented during the last year. As we outlined in the previous yearbook, these insulins where thought to be of particular value in insulin pump therapy. However, when the results of the Onset 5 FiAsp pump trial were presented during the 2017 ATTD meeting, the results were controversial. While we are still waiting for the eventual publication of this study, Eli Lilly initiated the PRONTO-Pump phase 3 trial to evaluate the compatibility and safety of their ultrarapid formulation LY 900014 or trepostinil lispro compared with insulin lispro in February 2018. Although clinical data of Adocia's ultra-rapid insulin-known as BioChaperone Lispro-was originally developed together with Lilly, this collaboration was terminated as we reported in last year's article. While initial data for treatment in people with type 1 and type 2 diabetes (T1D and T2D) have now been published, Adocia is still left without a partner to help get BioChaperone Lispro through critical phase 3 trials. Adocia won its first claim against Eli Lilly & Company regarding a disputed milestone payment, and additional claims will be assessed in another hearing, but a decision is not expected until 2019 and the future of the program remains unclear at this time. While the two ultra-long-acting basal insulin analogs, Toujeo (Sanofi) and Tresiba (Novo Nordisk) have now been on the market for several years, we are entering a time during which the efficacy in reducing the risk for hypoglycemia with the ultra-longacting insulins is studied in direct head-to-head randomized controlled trials and also with different methodologies including continuous glucose monitoring. As our review concludes, uncertainty still remains whether there are any clinically meaningful differences between the two at the present time. The first biosimilar insulin (BioIns)-an insulin glargine developed by Eli Lilly and Boehringer Ingelheim called Abasaglar in the EU and Basaglar in the United States (which was approved in the United States, but not as BioIns) has been on the market now for 1 to 2 years in the EU and the United States. It appears as if this BioIns has gained more market acceptance in the United States than in the EU; it is preferred over the originator insulin glargine in major U.S. formularies, which has induced significant reductions in the sales of the originator insulin. The observed decrease in prices varies between countries, with a maximum of up to 30%. Most likely, a plethora of BioInsparticularly insulin glargines-will be on the market within a few years, which might generate some confusion at the levels of both patients and health-care professionals. As we approach the centennial celebration of insulin discovery, the current scientific progress and controversies around the molecule remain thought-provoking. Key Articles Reviewed for the Article Effect of insulin degludec vs insulin glargine U100 on hypoglycemia in patients with type 1 diabetes. The SWITCH 1 randomized clinical trial

Diabetes Research and Clinical Practice, 2011

Diabetes Research and Clinical Practice, 2015

Diabetes Technology & Therapeutics, 2012

Several biopharmaceuticals, including insulin and insulin analogs, are, or shortly will be, off-patent, thereby providing an opportunity for companies to attempt to manufacture ''copies'' commonly referred to as biosimilars and also known as follow-on biologics. Reassurance that such copy biologics are equally safe and effective as the conventional products is essential. It is important for the clinician to consider what information is therefore necessary for such assurances. Biopharmaceuticals, produced from living organisms and manufactured by complex processes, differ in many respects from chemically derived drugs. The biological source materials and manufacturing processes for non-innovator biologics may differ considerably from those used for producing the innovator substance. Differences between innovator and non-innovator products can be identified analytically (e.g., batch-to-batch consistency, product stability along side clinical safety). This provides a strong argument for caution before automatic substitution of conventional products (e.g., insulin by biosimilars). Several non-innovator insulins, including insulin analogs (while still patent-protected), are already available in many countries. Many of these lack rigorous regulations for biosimilar approval and pharmacovigilance. Recently an application for a biosimilar recombinant human insulin was withdrawn by the European Medicines Agency because of safety and efficacy concerns. Therefore, every biosimilar insulin and insulin analog should be assessed by well-defined globally harmonized preclinical and clinical studies followed by post-marketing pharmacovigilance programs, in the interest of people with diabetes worldwide.

2012

Diabetology & Metabolic Syndrome, 2015

The development of extended-action insulin analogues was motivated by the unfavorable pharmacokinetic (PK) profile of the conventional long-acting insulin formulations, generally associated with marked inter and intra patient variability and site-and dose-dependent effect variation. The new ultra-long insulin analogue degludec (IDeg) has the same amino acid sequence as human insulin except for the removal of threonine in the position 30 of the B chain (Des-B30, "De") and the attachment, via a glutamic acid linker ("glu"), of a 16-carbon fatty diacid (hexadecanoic diacid, "dec") to lysine in the position 29 of the B chain. These modifications allow that, after changing from the pharmaceutical formulation to the subcutaneous environment, IDeg precipitates in the subcutaneous tissue, forming a depot that undergoes a highly predictable gradual dissociation. Thus, once-daily dosing of IDeg results in a low peak: trough ratio, with consequent low intra-individual variability and plasmatic concentrations less critically dependent upon the time of injections. The clinical development program of IDeg (BEGIN) was comprised of 9 therapeutic confirmatory trials of longer duration (26-52 weeks) and showed that the efficacy of IDeg is comparable to insulin glargine in type 1 (T1D) and type 2 (T2D) diabetes patients across different age, body mass index and ethnic groups. This new ultra-long insulin analogue presents as advantages flexibility in dose timing and lower risk of hypoglycemia.

2002

Diabetes/Metabolism Research and Reviews, 2014

SummaryInsulin remains the most effective and consistent means of controlling blood glucose levels in diabetes. Since 1946, neutral protamine Hagedorn (NPH) has been the predominant basal insulin in clinical use. However, absorption is variable due to the need for resuspension and the time–action profile (peak activity 4–6 h after subcutaneous administration) confers an increased propensity for between‐meal and nocturnal hypoglycaemia. In the 1980s, recombinant DNA technology enabled modifications to the insulin molecule resulting in the soluble long‐acting insulin analogues, glargine and detemir. Both exhibit a lower risk of hypoglycaemia compared with neutral protamine Hagedorn due to improved time–action profiles and reduced day‐to‐day glucose variability. Glargine is indicated for administration once daily and detemir once or twice daily. Degludec is the latest prolonged‐acting insulin which forms long subcutaneous multi‐hexamers that delay absorption. Recent phase III trials in...

QJM, 2002