Eli Lilly and Company, a global healthcare leader, has released phase III trial data of basal insulin peglispro (BIL) demonstrating statistically significantly lower haemoglobin A1c (HbA1c) compared to insulin glargine at 26 and 52 weeks in people with type 1 diabetes.

Detailed results from the IMAGINE-1 and IMAGINE-3 clinical trials were presented at the American Diabetes Association's (ADA) 75th scientific sessions in Boston. People with type 1 diabetes in these trials were also taking mealtime insulin.

BIL has a hepato-preferential activity profile derived from its reduced effect in peripheral tissue, making it more similar to endogenous insulin compared to other exogenous insulins with a conventional activity profile.

"In many people with type 1 diabetes, current insulin treatments may not be optimal for a variety of reasons," said Melanie Davies, M.D., professor of diabetes medicine, University of Leicester, United Kingdom. "Results from the IMAGINE trials showed that BIL has a unique combination of benefits, including superior glycemic control, reduced nocturnal hypoglycaemia and weight loss, all of which could be beneficial for people who need basal insulin treatment."

In IMAGINE-1 and IMAGINE-3, BIL demonstrated superiority in HbA1c compared to insulin glargine. Significantly more patients taking BIL met the ADA's recommended HbA1c target of less than 7 per cent and experienced lower rates of nocturnal hypoglycaemia compared to those taking insulin glargine. In both trials - in which patients were taking both mealtime and basal insulin - there was a statistically significant increase in the rate of total hypoglycaemia for patients taking BIL compared with those taking insulin glargine due to a higher rate of daytime hypoglycemic events.

In both trials, patients treated with BIL experienced mean weight loss compared to weight gain in patients who took insulin glargine.

In both trials, patients taking BIL had an increase in triglycerides compared to insulin glargine. In IMAGINE-3, patients taking BIL had an increase in LDL cholesterol, a decrease in HDL cholesterol and increases in systolic and diastolic blood pressure compared to insulin glargine. The rate of major adverse cardiac events MACE+ (cardiovascular death, non-fatal stroke, non-fatal MI and hospitalization due to unstable angina) was lower for patients taking BIL compared with those taking insulin glargine in IMAGINE-3. There were no MACE+ events in IMAGINE-1.

Additionally, in both studies, patients taking BIL had an increase in the liver enzyme ALT (alanine aminotransferase). Four weeks after BIL was discontinued these levels decreased toward baseline. Liver fat was measured by MRI in a subset of patients in both studies and was higher in patients treated with BIL compared to insulin glargine.

"These unprecedented results are meaningful not only to people with type 1 diabetes but also for those in the scientific and clinical community," said David Kendall, M.D., vice president, medical affairs, Lilly Diabetes.

"Lilly is committed to developing innovative treatments to help people with diabetes achieve their goals. To that end, we are excited to continue development of promising investigational treatments such as BIL."

Lilly also presented results from IMAGINE-7, a study investigating flexible dose-timing of BIL in people with type 1 diabetes. There was no statistically significant difference in HbA1c or nocturnal and total hypoglycaemia rates between people taking BIL dosed at variable times throughout the day.

BIL showed consistency in various measurements of glucose control across type 1 diabetes trials. Patients taking BIL showed lower HbA1c at the primary endpoints compared to those on insulin glargine in the IMAGINE-1 trial at 26 weeks (7.1 per cent vs. 7.4 per cent) and in the IMAGINE-3 trial at 52 weeks (7.4 per cent vs. 7.6 per cent).
Significantly more patients taking BIL reached the ADA's recommended target HbA1c of less than 7 per cent compared to insulin glargine in the IMAGINE-1 trial at the primary endpoint of 26 weeks (44.9 per cent vs. 27.5 per cent) and in the IMAGINE-3 trial at the 52- week primary endpoint (35.3 per cent vs. 26.1 per cent).

In both studies, patients taking BIL had lower rates of nocturnal hypoglycemia compared to insulin glargine: IMAGINE-1 at 26-week primary endpoint: 1.7 vs. 2.7 events/patient/30 days, IMAGINE-3 at 52-week primary endpoint: 1.3 vs. 2.5 events/patient/30 days.

Patients taking BIL had higher rates of total hypoglycemia compared to insulin glargine in IMAGINE-1 at the 26-week primary endpoint (16.0 vs. 12.4 events/patient/30 days) and in IMAGINE-3 at the 52-week primary endpoint (15.3 vs. 13.9 events/patient/30 days).1,2

In an integrated analysis of IMAGINE-1 and IMAGINE-3, there were no significant differences in rates of severe hypoglycemia between BIL and insulin glargine. However, patients taking BIL had higher rates of severe hypoglycemia compared to insulin glargine in IMAGINE-1 at 26 weeks (39.0 vs. 16.2 events/100 patient years) and similar rates of severe hypoglycemia compared to insulin glargine in IMAGINE-3 at 52 weeks (19.7 vs. 22.5 events/100 patient years).1,2

Patients taking BIL experienced mean weight loss while patients taking insulin glargine experienced mean weight gain in both IMAGINE-1 at the primary endpoint of 26 weeks (-1.2 kg vs. +0.7 kg) and IMAGINE-3 at the primary endpoint of 52 weeks (-0.6 kg vs. +1.2 kg).

In an integrated analysis of type 1 studies, patients taking BIL had a mean increase in the liver enzyme ALT compared to insulin glargine (the mean difference between treatment groups at 52 weeks was 7.2 IU/L). Four weeks after BIL was discontinued these levels decreased toward baseline. Additionally, more BIL-treated patients had an ALT level greater than or equal to three times the upper limit of normal compared to insulin glargine (ALT = 3X ULN: 4.4 per cent vs. 1.5 per cent). No cases of severe drug-induced liver injury (Hy's Law) occurred in these studies.

Liver fat was measured using magnetic resonance imaging (MRI) in a subset of patients from both studies. Results showed BIL-treated patients had an increase in liver fat content from baseline compared to those treated with insulin glargine (the mean difference between treatment groups was 2.2 percent at 52 weeks).

In the IMAGINE-7 trial, patients taking BIL experienced an increase in the level of ALT from baseline (10.59 IU/L), but four weeks after BIL was discontinued these levels decreased toward baseline. No patients met the criteria for severe drug-induced liver injury (Hy's Law) in the study.

In both IMAGINE-1 and IMAGINE-3, patients taking BIL had an increase in triglycerides. An analysis across all trials - including type 2 - showed that the rates of major adverse cardiovascular events among patients taking BIL and those taking insulin glargine or NPH insulin were similar, with an observed hazard ratio below 1 and the upper limit of the 95 per cent confidence interval below 1.4.

In IMAGINE-3, BIL-treated patients experienced small but statistically significant increases in systolic and diastolic blood pressure compared to insulin glargine patients (less than 2 mmHg mean difference at 52 weeks).

In IMAGINE-3, patients on BIL also had increases in LDL cholesterol levels and reductions in HDL cholesterol levels compared to those taking insulin glargine.

There were significantly more injection site reactions in patients treated with BIL than those treated with insulin glargine.

IMAGINE-1 is a phase III, 78-week (primary endpoint at 26 weeks), open-label, randomized, study of 455 patients designed to compare BIL (n=295) to insulin glargine (n=160) in combination with mealtime insulin in patients with type 1 diabetes. Patients were randomized to bedtime BIL (n=295) or insulin glargine (n=160). Patients in both groups had a mean baseline HbA1c of 7.8 per cent.

IMAGINE-3 is a phase III, 52-week, double-blind, randomized study of 1,114 patients with type 1 diabetes designed to compare BIL (n=664) to insulin glargine (n=450) in combination with mealtime insulin. Patients in both groups had a mean baseline HbA1c of 7.9 per cent.
IMAGINE-7 is a phase III, 36-week, randomized, crossover study of 212 patients designed to compare BIL administered once daily at a fixed time to BIL administered at a variable time of day in patients with type 1 diabetes. Patients were randomized to two 12-week treatment periods comparing fixed time dosing to variable time dosing. Patients had a mean baseline HbA1c of 7.5 per cent.

Basal insulin peglispro, discovered in Lilly Research Laboratories, is currently in phase III clinical trials and is being studied as a once-daily treatment for type 1 and type 2 diabetes. BIL is a hepato-preferential basal insulin. Its activity profile is derived from its reduced effect in peripheral tissue, making it more similar to endogenous insulin compared to other exogenous insulins with a conventional activity profile.    

In the clinical trial programme to date, consisting of more than 6,000 patients, approximately 3,900 patients have been treated with BIL. In the core phase III clinical trial programme consisting of seven IMAGINE trials in patients with type 1 and type 2 diabetes, superiority in HbA1c was seen in five trials for BIL against active comparators.

Approximately 29 million Americans and an estimated 387 million people worldwide have type 1 and type 2 diabetes. Type 2 diabetes is the most common type, accounting for an estimated 90 to 95 per cent of all diabetes cases. Diabetes is a chronic disease that occurs when the body either does not properly produce, or use, the hormone insulin.