Development of new basal insulin peglispro (LY2605541) ends in a disappointing result

LAPSInsulin115: A novel ultra‐long‐acting basal insulin with a unique action profile

“…Insulin degludec and insulin glargine come closer to the ideal of creating a peakless basal insulin, and have to be injected once daily. The attempt to create a hepato‐preferential insulin analogue with an increased half‐life of up to 24 to 45 hours by PEGylation of insulin lispro was stopped at the end of clinical phase III because of an increase in liver fat observed in the IMAGINE trials . Further formats of basal insulin analogues are under development to reduce injection frequency and, thus, to create a more convenient therapy and to improve quality of life for people with diabetes.…”

Structural Perspectives of Insulin Receptor Isoform-Selective Insulin Analogs

“…The increase in molecular size of the analog appeared to alter its tissue distribution in favor of liver versus peripheral tissues ( 8 ). However, in 2015, Eli Lilly and Company made the decision to halt the peglispro development program, because the phase III trials reported elevated alanine transaminases and increased fat in the liver ( 9 ).…”

Targeting insulin to the liver corrects defects in glucose metabolism caused by peripheral insulin delivery

“…Under such conditions it is possible that unrestrained hepatic FFA uptake could lead to hepatic lipid accumulation (61). Indeed, the development of a promising hepato-preferential insulin analog (LY2605541) (8,62) was recently ended prior to its entry into phase III trials after elevated alanine transaminases and in some cases increased hepatic fat content were observed in treated individuals (63). Although the insulin-327 analog used in our study is a model compound not intended for clinical use, the differential effects of hepato-preferential insulin analogs on liver and fat should be considered in their development.…”