How Can a Good Idea Fail? Basal Insulin Peglispro [LY2605541] for the Treatment of Type 2 Diabetes

Muñoz-Garach, Araceli; Molina-Vega, María; Tinahones, Francisco J.

doi:10.1007/s13300-016-0214-7

Cited by 33 publications

(20 citation statements)

References 29 publications

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“…In addition to the advantages that this type of distribution would have to minimize the risk of hypoglycaemia due to variations in oral absorption (see section below on hypoglycaemia assessment), it could be speculated that an insulin analogue with strong albumin binding having a rapid, peaked central (blood compartment) PK profile would mimic the pattern of insulin secreted from the pancreas directly into the portal circulation where the liver is highly exposed. This peaked PK profile upon oral delivery with greater liver effect is not expected to be the same as what was observed for insulin PEGlispro which demonstrated a constant hepato-selective effect 16 . Whether this more physiological profile of rapid and peaked insulin delivery to the liver (part of the blood compartment due to the fenestrated capillaries) would lead to improved metabolic control remains to be determined.…”

Section: Resultsmentioning

confidence: 55%

Molecular engineering of safe and efficacious oral basal insulin

et al. 2020

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Recently, the clinical proof of concept for the first ultra-long oral insulin was reported, showing efficacy and safety similar to subcutaneously administered insulin glargine. Here, we report the molecular engineering as well as biological and pharmacological properties of these insulin analogues. Molecules were designed to have ultra-long pharmacokinetic profile to minimize variability in plasma exposure. Elimination plasma half-life of ~20 h in dogs and ~70 h in man is achieved by a strong albumin binding, and by lowering the insulin receptor affinity 500-fold to slow down receptor mediated clearance. These insulin analogues still stimulate efficient glucose disposal in rats, pigs and dogs during constant intravenous infusion and euglycemic clamp conditions. The albumin binding facilitates initial high plasma exposure with a concomitant delay in distribution to peripheral tissues. This slow appearance in the periphery mediates an early transient hepato-centric insulin action and blunts hypoglycaemia in dogs in response to overdosing.

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Section: Resultsmentioning

confidence: 55%

Molecular engineering of safe and efficacious oral basal insulin

et al. 2020

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“…Another ultra-long-acting basal insulin, PegLispro, demonstrated clinically relevant improvements in glycaemic efficacy with significant reduction in nocturnal hypoglycaemia compared to NPH insulin in phase 3 trials 7 but this was discontinued in 2017 due to adverse effects including insulin site reactions and abnormal liver transaminase and triglyceride levels. 8 Effective insulin therapy improves glycaemic control and reduces the development and progression of complications. However, hypoglycaemia and weight gain are significant adverse effects of insulin therapy.…”

Section: Background and Rationale For Development Of Concentrated Insmentioning

confidence: 99%

Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes

Chatterjee

Khunti

Davies

2019

Drugs

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The recent introduction of the second generation long-acting analogue insulins degludec and insulin glargine U300 have increased the choice of basal insulin therapy for patients with type 2 diabetes. The pharmacokinetic and pharmacodynamic properties of these insulins result in a flatter profile which lasts over 24 hours and provides an increased window of administration of six hours once daily. Large scale multicentre randomised clinical trial programmes (BEGIN for degludec U100 and U200 and EDITION for glargine U300) evaluating these insulin therapies against glargine U100 have demonstrated that they are either non-inferior or superior for glycaemic efficacy and safety but less likely to result in severe or nocturnal hypoglycaemia than glargine U100. The disposable pen devices for these insulins have been designed with patient satisfaction and convenience in mind. No concerns have arisen with adverse events with insulin analogues or cardiovascular safety from the ORIGIN and DEVOTE trials. As they demonstrate equivalent glycaemic efficacy to other basal insulins, they should be considered more in selected patient groups including those with recurrent or increased risk of hypoglycaemia, especially severe or nocturnal episodes, in the elderly or those living alone, and in patients with multiple co-morbidities such as cardiovascular or renal disease. Key Points • Second generation basal insulin analogues have demonstrated equivalent glycaemic efficacy to earlier basal insulin therapies but may result in lower risk of hypoglycaemia. • Selected patient groups at increased risk of hypoglycaemia such as elderly, those living alone or with multiple co-morbidities including cardiovascular or renal disease may be considered for treatment with insulin degludec or glargine U300.

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“…This product had clear liver-preferred action, with less weight gain and a trend to reduced hypoglycaemia risk, in particular nocturnal hypoglycaemia, as compared with glargine U100. However, the development of this programme was halted due to liver enzyme rises, suggesting direct liver damage [45]. At present, several liver-preferred insulins are still in development.…”

Section: The Future For Insulin and Hypoglycaemiamentioning

confidence: 99%

Minimising hypoglycaemia in the real world: the challenge of insulin

Mathieu

2021

Diabetologia

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Insulin therapy has been a life saver for people with type 1 diabetes and has been an essential tool in the therapy of people with type 2 diabetes, but the risk for hypoglycaemia has been a major hurdle to achieving good glycaemic control for most. Insulin analogues, the availability of novel technologies for the administration of insulin, like insulin pumps, and, in particular, tools to measure glucose levels, evolving from capillary measurements to continuous glucose monitoring, have revolutionised the way in which people living with diabetes use insulin. Novel insulin concepts, like once-weekly or oral insulin administration, will have to demonstrate safety on the side of hypoglycaemia before they will be able to move into the clinic.

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How Can a Good Idea Fail? Basal Insulin Peglispro [LY2605541] for the Treatment of Type 2 Diabetes

Cited by 33 publications

References 29 publications

Molecular engineering of safe and efficacious oral basal insulin

Molecular engineering of safe and efficacious oral basal insulin

Achieving Glycaemic Control with Concentrated Insulin in Patients with Type 2 Diabetes

Minimising hypoglycaemia in the real world: the challenge of insulin

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