Pharmacokinetics of the Long‐Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function

Linnebjerg, Helle; Choi, Siak Leng; Lam, Eric Chen Quin; Mace, Kenneth F.; Hodgson, Teri S.; Sinha, Vikram

doi:10.1002/cpdd.252

Cited by 6 publications

(6 citation statements)

References 12 publications

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“…These results suggested that hydrodynamic size and not molecular weight was also the prominent determinant of glomerular filtration for BIL, since the molecular weight of BIL is much lower than that of albumin (66 kDa) and is not filtered by the glomerulus under normal physiological conditions. The observations noted in the 5/6 nephrectomized rats were later confirmed in humans with varying degrees of renal impairment …”

Section: Receptor Binding Pharmacology and Mechanism Of Action Of Bilmentioning

confidence: 71%

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Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

Jacober

Prince

Beals

et al. 2016

Diabetes Obesity Metabolism

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).Basal insulin peglispro (BIL) is a novel basal insulin with a flat, prolonged activity profile. BIL has been demonstrated in a dog model, in healthy men and in patients with type 1 diabetes (T1D) to have significant hepato-preferential action resulting from reduced peripheral activity. In the IMAGINE-Phase 3 clinical trial program, more than 6000 patients were included, of whom 3900 received BIL. Of the 7 pivotal IMAGINE trials, 3 studies were double-blinded and 3 were in T1D patients. BIL consistently demonstrated a greater HbA1c reduction, less glycaemic variability and a clinically relevant reduction in the rates of nocturnal hypoglycaemia across comparator [glargine and isophane insulin (NPH)] studies. Trials using basal/bolus regimens had higher rates of total hypoglycaemia with BIL due to higher rates of daytime hypoglycaemia.Severe hypoglycaemia rates were similar to comparator among both patients with T1D or type 2 diabetes (T2D). T1D patients lost weight compared with glargine (GL). Patients with T2D tended to gain less weight with BIL than with glargine. Compared to glargine, BIL was associated with higher liver fat, triglycerides and alanine aminotransferase (ALT) levels, including a higher frequency of elevation of ALT ≥3 times the upper limit of normal, but without severe, acute drug-induced liver injury. Injection site reactions, primarily lipohypertrophy, were more frequent with BIL. In conclusion, BIL demonstrated better glycaemic control with reduced glucose variability and nocturnal hypoglycaemia but higher triglycerides, ALT and liver fat relative to conventional comparator insulin. The hepato-preferential action of BIL with reduced peripheral activity may account for these findings. K E Y W O R D Sbasal insulin, drug development, drug mechanism, hypoglycaemia, insulin therapy Insulin therapy has long been a mainstay of therapy for type 1 and

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Section: Receptor Binding Pharmacology and Mechanism Of Action Of Bilmentioning

confidence: 71%

“…The observations noted in the 5/6 nephrectomized rats were later confirmed in humans with varying degrees of renal impairment. 34…”

Section: Introductionmentioning

confidence: 99%

Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

Jacober

Prince

Beals

et al. 2016

Diabetes Obesity Metabolism

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“…It showed that clearance of lispro protamine was significantly reduced in renal impairment, but with no effect on the clearance of BIL keeping its glucose-lowering properties. This observation occurred because of BIL’s increased hydrodynamic size, which reduced renal ultrafiltration [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

“…In patients undergoing dialysis, BIL did not appear to be significantly eliminated, less than 25%. They concluded BIL was well tolerated in patients with different degrees of renal function and with no need to reduce the dose [ 14 ].…”

Section: Methodsmentioning

confidence: 99%

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

2016

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IntroductionLack of control in diabetic patients has stimulated the development of new insulin analogues. One of these was basal insulin peglispro (BIL) or LY2605541; it had a large hydrodynamic size, flat pharmacokinetic profile, half life of 2–3 days and acted preferably in the liver.MethodsWe reviewed the recent literature examining the pharmacokinetics, pharmacodynamics, efficacy and safety of BIL treatment in type 2 diabetes patients.ResultsThe pharmacodynamic and pharmacokinetic outline of BIL seemed to have an advantage over neutral protamine Hagedorn and glargine insulins. Recently, phase 3 studies suggested BIL was superior to glargine in reducing glucose levels in type 1 and type 2 diabetes patients in addition to causing less weight gain. It showed a different hypoglycaemia rate profile depending on the study population, with less nocturnal hypoglycaemia compared to glargine. Unfortunately, it caused higher transaminase and triglyceride levels, which led the company to discontinue development. The decision came after it had been analysed by the regulatory authorities and other external experts concerning the worse liver profile data from the IMAGINE trials.ConclusionsBIL was an adequate basal insulin analogue with interesting specific properties. Unfortunately the disadvantages as shown in the lipid values and liver function tests led to its failure.

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“…LY2605541 has a lower binding affinity for the insulin receptor and insulin‐like growth factor‐1 receptor than lispro, and a lower mitogenic potency than human insulin . The half‐life is 24–45 h and duration of action exceeds 36 h , and are unaffected by renal impairment . Animal studies suggest that LY2605541 may have a hepatoselective action on glucose metabolism [].…”

Section: New Prolonged Insulin Analoguesmentioning

confidence: 99%

Basal insulin analogues in the management of diabetes mellitus: what progress have we made?

Owens

Matfin²,

Monnier³

2014

Diabetes Metabolism Res

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Insulin 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 type 1 and type 2 diabetes show that degludec was non-inferior to comparators (predominantly glargine) with a minimal although inconsistent reduction in overall hypoglycaemia and a small absolute difference in nocturnal hypoglycaemia. Newer developmental agents include LY2605541 and glargine U300. LY2605541 comprises insulin lispro combined with polyethylene glycol, thereby increasing its hydrodynamic size and retarding absorption from the subcutaneous tissue. Glargine U300 is a new formulation of glargine resulting in a flatter and more prolonged time-action profile than its predecessor. This article reviews recent advances in basal insulin analogues, including a critical appraisal of the degludec trials.

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Pharmacokinetics of the Long‐Acting Basal Insulin LY2605541 in Subjects With Varying Degrees of Renal Function

Cited by 6 publications

References 12 publications

Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

Basal insulin peglispro: Overview of a novel long‐acting insulin with reduced peripheral effect resulting in a hepato‐preferential action

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

Basal insulin analogues in the management of diabetes mellitus: what progress have we made?

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