Critical appraisal of the safety and efficacy of insulin detemir in glycemic control and cardiovascular risk management in diabetics

Abstract

Insulin detemir is an analog of human insulin designed to provide a long duration of basal insulin action. This is achieved by protracted absorption from the injection depot, which results in part from increased self-association of insulin detemir molecules and in part from reversible albumin binding. Subsequent albumin binding in the circulation is thought to buffer changes in the effects at target tissues that could otherwise arise from variability in absorption rate. In consequence, insulin detemir has shown a less variable pharmacodynamic profile than alternative basal insulins; this manifests as more consistent temporal glucose reduction profiles in repeat-clamp studies. In clinical trials, insulin detemir has been characterized by consistent risk reductions in hypoglycemia, as well as reduced weight gain in comparison with other basal insulins. Given some recent associations that have been made in prospective and epidemiologic studies between glucose variability and/or hypoglycemia and increased cardiovascular risk, and the long-known association between excess weight and cardiovascular risk, it is possible that the clinical profile of insulin detemir may carry prognostic value with regard to cardiovascular safety, although this is yet to be substantiated. There have also been some concerns raised recently over the use of insulin analogs and cancer risk, but available clinical data and the receptor interaction profile of insulin detemir suggest no excess in risk in comparison with human insulin therapy. Optimal approaches for the clinical use of insulin detemir have been emerging through an increasing clinical study base, and the analog is becoming established as a potentially valuable therapy option.

Peptide Lipidation – A Synthetic Strategy to Afford Peptide Based Therapeutics

“…Peptide backbone modifications, cyclization, unnatural amino acid insertion, PEGylation, glycosylation, phosphorylation and lipidation are common techniques to improve the physicochemical and pharmacological profiles of bioactive peptides. (Zhang and Bulaj 2012) Peptide lipidation is an effective strategy to modify the pharmacokinetic and pharmacodynamic properties of lead peptide therapeutics and has proven to be successful with several marketed peptides including liraglutide (Victoza ® ) (Jackson et al 2010;Knudsen et al 2000) and insulin detemir (Levemir ® ) (Zhang and Bulaj 2012;Home and Kurtzhals 2006;Le Floch 2010). Incorporation of lipid units onto a peptide backbone can dramatically increase enzymatic stability (Simerska et al 2011), receptor selectivity and potency (Ward et al 2013), bioavailability (Hamman et al 2005;Park et al 2011;Renukuntla et al 2013;Karsdal et al 2015) and drug delivery potential (membrane permeability) (Zhang and Bulaj 2012;Simerska et al 2011).…”

Fatty acylation enhances the cellular internalization and cytosolic distribution of a cystine-knot peptide

“…Fatty acylation has drawn considerable interest in the field of peptide drug development due to its impact on the pharmacokinetics of biotherapeutics, in particular extending the systemic half-life of drugs via promoting their binding to serum albumin ( Kowalczyk et al., 2017 ; Myers et al., 1997 ). Examples of marketed fatty acylated peptide therapeutics used in diabetic patients include long-acting insulin detemir (Levemir) ( Home and Kurtzhals, 2006 ; Le Floch, 2010 ), which is myristoylated, and glucagon-like peptide-1(GLP-1) receptor agonist liraglutide (Victoza) ( Jackson et al., 2010 ; Knudsen et al., 2000 ), which is N-palmitoylated. Although the effects of fatty acylation on the pharmacokinetic behavior and serum binding of peptide drugs have been extensively studied, their impact on delivery to the cytosol remains elusive.…”