Better Glycemic Control and Weight Loss With the Novel Long-Acting Basal Insulin LY2605541 Compared With Insulin Glargine in Type 1 Diabetes

Abstract

OBJECTIVETo compare effects of LY2605541 versus insulin glargine on daily mean blood glucose as part of a basal-bolus regimen for type 1 diabetes.RESEARCH DESIGN AND METHODSIn this randomized, Phase 2, open-label, 2 × 2 crossover study, 137 patients received once-daily basal insulin (LY2605541 or glargine) plus mealtime insulin for 8 weeks, followed by crossover treatment for 8 weeks. Daily mean blood glucose was obtained from 8-point self-monitored blood glucose profiles. The noninferiority margin was 10.8 mg/dL.RESULTSLY2605541 met noninferiority and superiority criteria compared with insulin glargine in daily mean blood glucose (144.2 vs. 151.7 mg/dL, least squares mean difference = −9.9 mg/dL [90% CI −14.6 to −5.2], P < 0.001). Fasting blood glucose variability and A1C were reduced with LY2605541 compared with insulin glargine (both P < 0.001). Mealtime insulin dose decreased with LY2605541 and increased with insulin glargine. Mean weight decreased 1.2 kg with LY2605541 and increased 0.7 kg with insulin glargine (P < 0.001). The total hypoglycemia rate was higher for LY2605541 (P = 0.04) and the nocturnal hypoglycemia rate was lower (P = 0.01), compared with insulin glargine. Adverse events (including severe hypoglycemia) were similar, although more gastrointestinal-related events occurred with LY2605541 (15% vs. 4%, P < 0.001). Mean changes (all within normal range) were higher for alanine aminotransferase, aspartate aminotransferase, triglycerides, and LDL-cholesterol and lower for HDL-cholesterol with LY2605541 compared with insulin glargine (all P < 0.02).CONCLUSIONSIn type 1 diabetes, compared with insulin glargine, LY2605541, a novel, long-acting basal insulin, demonstrated greater improvements in glycemic control, increased total hypoglycemia, and reduced nocturnal hypoglycemia, as well as reduced weight and lowered mealtime insulin doses.

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. This adaptation may, however, result in a loss of superiority in terms of efficacy compared with standard insulin glargine and perhaps unmask an insufficient efficacy at peripheral muscle and adipose tissues, as might be evidenced by increased lipolysis and some loss of body weight (19,50,51,57). This aspect clearly needs more evaluation, especially since 1 unit of insulin PegLispro contains 9 nmol insulin in contrast to 6 nmol in insulins degludec or glargine U300.…”

“…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). A significant lower rate of nocturnal hypoglycemia in the range of 36-45% has been observed compared with that in those taking insulin glargine U100 (1,3,4,15,20,21,50-52).…”

“…These have demonstrated that PegLispro was consistently superior under these conditions to glargine in terms of lowering HbA 1c and in causing less nocturnal hypoglycemia with a reduction of ;40% (20,21,50-52). However, an increase in liver enzyme levels (alanine aminotransferase) with an increase in liver fat content has been noted, although no acute, severe, hepatocellular drug-induced liver injury has been observed to date with PegLispro in studies up to 78 weeks (20,21,51,53).…”

Role of insulin in management of type 2 diabetes mellitus

“…97,98 Similar outcomes were observed in those receiving lixisenatide as add-on therapy to basal insulin. [99][100][101] A product IDegLira (Novo Nordisk Inc) contains a fixed ratio of 1 unit of degludec and 0.036 mg of liraglutide per unit drug. The combination product showed superior HbA1C reductions as compared with insulin degludec or liraglutide alone, each as an addition to metformin with or without pioglitazone.…”