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Novel liver-targeted insulin comparable to insulin lispro in type 1 diabetes
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Adults with type 1 diabetes assigned to a mealtime, liver-targeted insulin using hepatocyte-directed vesicle technology for 6 months experienced a similar reduction in HbA1c when compared with similar adults assigned to insulin lispro, according to findings published in Diabetes Care.
In reporting findings from the phase 2b Insulin Liver Effect (ISLE-1) trial, the researchers also found that participants with a high baseline HbA1c assigned to hepatocyte-directed vesicle (HDV) insulin lispro experienced similar HbA1c reductions while using 25% less mealtime insulin with less hypoglycemia. HDV technology is designed to be mixed with any commercially available insulin to improve glycemic response, according to Diasome Pharmaceuticals.
“Hepatocyte directed vesicle technology is the only additive in development that targets injected insulin to the liver, a key organ in blood glucose regulation,” David C. Klonoff, MD, FACP, FRCPE, clinical professor of medicine at the University of California San Francisco and medical director of the Diabetes Research Institute at Mills-Peninsula Medical Center in San Mateo, California, told Endocrine Today. “In people without diabetes, the liver stores and releases glucose in the right amount and at the right time in response to insulin signals. HDV technology delivers insulin where it needs to go in order to be effective, thereby making injected insulin behave more physiologically in people with type 1 diabetes. HDV lispro describes a mixture of HDV plus mealtime insulin lispro, but HDV is designed to be added to any commercially available insulin. HDV insulin is also designed to be fully compatible with any delivery method, including insulin pump systems.”
Klonoff and colleagues analyzed data from 176 adults with type 1 diabetes with an HbA1c of at least 7% treated with multiple daily injections (basal insulin glargine or insulin detemir). Researchers randomly assigned patients to HDV insulin lispro (n = 118; 62% men; mean age, 47 years; mean baseline HbA1c, 8.12%) or insulin lispro alone (Humalog, Eli Lilly; n = 58; 72% men; mean age, 44 years; mean baseline HbA1c, 8.22%) along with masked continuous glucose monitoring for 5 to 7 days at baseline, week 13 and week 26. HbA1c, lipids and liver enzymes were measured monthly. Primary outcome was HbA1c noninferiority.
Similar HbA1c, insulin dose
At 26 weeks, mean change in HbA1c from baseline was 20.09% for participants in the HDV lispro group and 20.16% for participants in the insulin lispro group, for an estimated treatment difference of 0.09% (95% CI, 0.18-0.35), confirming noninferiority for HDV lispro. The researchers did not observe between-group differences from baseline through week 26 for basal, bolus or total insulin doses.
At week 26, mean basal doses were 0.36 U/kg per day for the HDV lispro group and 0.43 U /kg per day for the insulin lispro group. Mean bolus doses were 0.33 U/kg per day and 0.38 U/kg per day for HDV lispro and insulin lispro groups, respectively, and total insulin doses for the two groups were 0.66 and 0.76 U/kg per day, respectively.
There were no between-group differences observed for measures of hypoglycemia; median percentage of time spent below 54 mg/dL as determined by CGM during week 26 was 1.6% for the HDV lispro group and 1.5% for the insulin lispro group.
In analyses stratified by HbA1c, participants with HbA1c of at least 8.5% experienced comparable HbA1c reductions (0.5%) for both treatments at week 26; however, participants in the HDV lispro group used 25% less bolus insulin vs. participants in the insulin lispro group and spent less time in hypoglycemia, according to researchers. Participants with a baseline HbA1c of less than 8.5% did not experience a change in HbA1c during the study or a difference in insulin dose on either treatment.
“Thus, at higher baseline HbA1c, there was less hypoglycemia and lower insulin dosing with similar HbA1c outcomes during HDV lispro vs. [insulin lispro], whereas greater risk of hypoglycemia despite similar HbA1c outcomes and insulin doses were observed with lower baseline HbA1c,” the researchers wrote.
HDV lispro was also associated with reduced total cholesterol when compared with insulin lispro (mean treatment difference, –0.31 mmol/L; P = .01). There were no between-group differences in liver function tests, and no participants experienced severe adverse events.
“Type 1 diabetes outcomes have not improved in recent years, despite adoption of technologies like insulin pumps and continuous glucose monitors,” Klonoff said. “HDV is the only injectable treatment option being developed to target the liver to better restore normal physiology and potentially allow people with type 1 diabetes to experience improved blood glucose control.”
‘Restoring normal physiology’
The researchers noted that outcomes in both HbA1c groups support the increased liver effect of HDV lispro.
“We believe that HDV technology, an additive that is designed to be mixed with any commercially available insulin, has the potential to be the first insulin therapy that enables decreased hypoglycemia risk by delivering mealtime insulin to the liver and restoring more normal physiology,” Robert Geho, chief executive officer of Diasome, said in the release. “Our enthusiasm is supported by the results of this clinical trial, which demonstrated HDV’s ability to simultaneously reduce HbA1c levels from baseline and decrease hypoglycemia risk in patients with high baseline HbA1c levels. If these results continue in our upcoming phase 3 trial, patients taking insulin should benefit from not having to make a trade-off choice between lower HbA1c levels and less hypoglycemia risk.”
Klonoff said Diasome is currently conducting a phase 2 study to identify the optimal dosing for HDV mixed with mealtime insulin for people with type 1 diabetes who have baseline HbA1c levels between 6.5% and 8.5%. Diasome also is planning to initiate phase 3 testing in 2020, he said. – by Regina Schaffer
For more information:
David C. Klonoff, MD, FACP, FRCPE, can be reached at the Diabetes Research Institute, Mills-Peninsula Medical Center, 100 S. San Mateo Drive, Room 5147, San Mateo, CA 94401; email: dklonoff@diabetestechnology.org.
Disclosures: Diasome Pharmaceuticals funded this study and provided editorial assistance. Klonoff reports he is a consultant for Abbott, Ascensia, EOFlow, Intarcia, Know, Lifecare, Novo Nordisk and Voluntis, and has received research funding from Diasome Pharmaceuticals, Lexicon and Novo Nordisk. Please see the study for all others authors’ relevant financial disclosures.
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