Basal Insulin Peglispro Demonstrates Preferential Hepatic Versus Peripheral Action Relative to Insulin Glargine in Healthy Subjects

Abstract

OBJECTIVEWe evaluated the endogenous glucose production (EGP) and glucose disposal rate (GDR) over a range of doses of basal insulin peglispro (BIL) and insulin glargine in healthy subjects. RESEARCH DESIGN AND METHODSThis was a single-center, randomized, open-label, four-period, incomplete-block, crossover study conducted in eight healthy male subjects. Subjects had 8-h euglycemic clamps performed with primed, continuous infusions of BIL (5.1 to 74.1 mU/min) in three dosing periods and insulin glargine (20 or 30 mU/m 2 /min) in a fourth period, targeted to achieve 50-100% suppression of EGP. D-[3-3 H] glucose was infused to assess rates of glucose appearance and disappearance. RESULTSMean BIL and insulin glargine concentrations (targeted to reflect the differences in intrinsic affinities of the two basal insulins) ranged from 824 to 11,400 and 212 to 290 pmol/L, respectively, and increased accordingly with increases in dose. Suppression of EGP and stimulation of GDR were observed with increasing concentrations of both insulins. At insulin concentrations where EGP was significantly suppressed, insulin glargine resulted in increased GDR. In contrast, at comparable suppression of EGP, BIL had minimal effect on GDR at lower doses and had substantially less effect on GDR than insulin glargine at higher doses. CONCLUSIONSThe novel basal insulin analog BIL has relative hepatopreferential action and decreased peripheral action, compared with insulin glargine, in healthy subjects.In vivo, insulin is secreted from pancreatic b-cells and enters the circulation via the portal vein, where on first pass the liver extracts ;40-80% (1-7). As a result, systemic circulating insulin levels are reduced compared with those in the portal vein, and subsequent insulin action in the peripheral target tissues is also reduced compared with the liver. Consequently, the relative ratio of hepatic action to peripheral action ranges between 2:1 and 4:1 (1,2,4,8-10). In contrast, when exogenous insulin is administered peripherally, insulin is distributed equally across the liver and peripheral tissues (11,12) and thus does not mimic normal physiology.

Weight‐sparing effect of insulin detemir: a consequence of central nervous system‐mediated reduced energy intake?

“…Also of note, a recent study in healthy subjects demonstrated preferential hepatic versus peripheral action of a novel, large basal insulin analogue (insulin peglispro) compared with insulin glargine. Initial results suggest that this insulin is also weight‐sparing 67. This provides further evidence that hepatoselectivity may indeed be an important mechanism contributing to the weight‐sparing effect of insulin detemir.…”

New Long-Acting Basal Insulins: Does Benefit Outweigh Cost?

“…PegLispro achieves a statistically significantly greater improvement in glycemic control than insulin glargine, and the risk of nocturnal hypoglycemia is reduced by nearly half compared with insulin glargine (1,3,4,15,20,21,43,51). However, daytime hypoglycemic events were significantly increased, possibly due to its hepato-preferential action resulting in a greater inhibition of hepatic glucose output postprandially (20,49). It remains to be seen whether a reduction in the dose of short-acting insulin or other hypoglycemic agents may abolish this untoward daytime hypoglycemia risk.…”

“…There is also a lesser variability in glucose lowering with PegLispro compared with insulin glargine (56) accompanied by less weight gain and fewer nocturnal hypoglycemic episodes in early phase 2 studies with PegLispro in both type 1 (51) and type 2 diabetes (21,50,56). Its preferential hepatic (inhibition of glucose production) versus peripheral (glucose disposal) activity makes it perhaps more similar to endogenous insulin when compared with other exogenously administered insulins that possess a predominant effect on peripheral glucose disposal (1,3,4,15,20,21,49). In a series of phase 3 studies (IMAGINE), it shows a consistent, although marginal, but statistically greater HbA 1c -lowering capacity (0.2-0.3% HbA 1c ) than glargine U100 in persons with either type 1 or type 2 diabetes on intensified insulin therapy or persons with type 2 diabetes on basal insulin in addition to oral therapy (20,51,52).…”

“…It possesses a prolonged duration of action exceeding 36 h as a result of delayed absorption and reduced clearance, with a low intrasubject variability in glucose lowering and a lower and quite different tissue distribution compared with the other insulin preparations (45,47,48). Both animal and human studies suggested that PegLispro may have a preferential hepato-specific action on glucose metabolism compared with insulin glargine (49). Early phase 3 clinical studies (IMAGINE) include eight pivotal studies, three of which are doubleblind, and most involve glargine (U100) as the comparator.…”

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

“…In the phase I study, LY2605541 showed flat PK and PD profiles accompanied by glucose normalization, prandial insulin dose reduction, and no severe hypoglycemia [7]. In addition to the long and flat PK/PD profile, LY2605541 demonstrates preferential hepatic versus peripheral action relative to insulin glargine in healthy individuals [8]. In this euglycemic clamps study, insulin glargine resulted in increased glucose disposal rate (GDR) at insulin concentrations where endogenous glucose production (EGP) was significantly suppressed.…”