Basal insulin peglispro reduces HbA1c in type 1 diabetes, increases ALT, liver fat

BOSTON — Patients with type 1 diabetes already prescribed mealtime insulin experienced greater reductions in HbA1c with basal insulin peglispro than with Lantus, and more of them reached the American Diabetes Association’s recommended HbA1c target of less than 7%, according to data from the phase 3 IMAGINE 1 and IMAGINE 3 clinical trials presented here.

Insulin peglispro (Eli Lilly) also was associated with an elevation in the liver enzyme alanine aminotransferase (ALT) and increased liver fat.

“To the best of my knowledge, this is the first registration trial of an insulin analogue ... that clearly shows the primary endpoint, or if you can extend it to 1.5 years, that clearly there was a significant improvement in A1c. Not only did we achieve noninferiority very easily, but it was definitely better than insulin glargine,” Satish S. Garg, MD, of the University of Colorado, Denver, said in a presentation.

In the 78-week, phase 3, open-label, randomized IMAGINE 1 trial, Garg and colleagues randomly assigned 455 patients (51% women) with type 1 diabetes (HbA1c < 12%) to insulin peglispro (n = 295) or Lantus (insulin glargine, Sanofi Aventis; n = 160) to be taken at bedtime.

In the 52-week, double blind, randomized IMAGINE 3 trial, Richard M. Bergenstal, MD, of Park Nicollet in Minneapolis, and colleagues randomly assigned 1,114 adults (39% women) with type 1 diabetes in a 3:2 ratio to bedtime insulin peglispro or insulin glargine.

In both studies, patients assigned insulin peglispro had lower HbA1c compared with insulin glargine (at week 78 in IMAGINE 1: 7.4% vs. 7.7%, P = .002; at week 52 in IMAGINE 3: 7.4% vs. 7.6%, P < .001). More patients reached the HbA1c target of less than 7% in the insulin peglispro groups compared with insulin glargine (at week 78 in IMAGINE 1: 34.5% vs. 22.9%, P = .002; at week 52 in IMAGINE 3: 35.3% vs. 26.1%, P < .001).

In both studies, patients assigned insulin peglispro had lower rates of nocturnal hypoglycemia (at week 78 in IMAGINE 1: 1.6 vs. 2.3 events/patient/30 days, P < .001; at week 52 in IMAGINE 3: 1.3 vs. 2.5 events/patient/30 days, P < .001), but higher rates of total hypoglycemia (at week 78 in IMAGINE 1: 14.3 vs. 11.4 events/patient/30 days, P < .001; at week 52 in IMAGINE 3: 15.3 vs. 13.9 events/patient/30 days, P = .002).

“As you would expect because [insulin peglispro] is an insulin that is much more stable and much longer acting, nocturnal hypoglycemia ... was significantly lower as compared with insulin glargine; however, total hypoglycemia was significantly higher in the [insulin peglispro] group,” Garg said. “Severe hypoglycemia ... was clearly related to the bolus insulin dose.”

Patients assigned insulin peglispro in both trials also lost weight compared with a weight gain in

patients assigned insulin glargine (at week 78 in IMAGINE 1: –0.9 vs. +1 kg, P < .001; at week 52 in IMAGINE 3: –0.6 vs. +1.2 kg, P < .001).

Additionally, in both studies, patients assigned insulin peglispro had an increase in the liver enzyme ALT (at week 78 in IMAGINE 1: 28.3 vs. 21.3 IU/L, P < .001; at week 52 in IMAGINE 3: 29.9 vs. 23.4 IU/L, P < .001). Further, at week 52 in IMAGINE 3, more insulin peglispro patients had ALT at least three times the upper limit of normal (4.8% vs. 2%, P = .021), with no cases of Hy’s Law. After 4-weeks’ discontinuation, ALT levels decreased toward baseline.

In a subset of 182 patients from both studies, liver fat content, measured by MRI, was higher in patients assigned insulin peglispro compared with insulin glargine (at week 78 in IMAGINE 1: 6.1% vs. 2.9%, P = .001; at week 52 in IMAGINE 3: 5.7% vs. 3.5%, P < .001). – by Jill Rollet

Reference s :

Garg SK, et al. Abstract 95-OR. Presented at: American Diabetes Association’s 75th Scientific Sessions; June 5-9, 2015; Boston.

Bergenstal RM, et al. Abstract 986-P. Presented at: American Diabetes Association’s 75th Scientific Sessions; June 5-9, 2015; Boston.

Disclosure s : Garg reports financial relationships with Eisai Co., Ltd., Eli Lilly and Company, Halozyme Therapeutics, JAEB Center, Juvenile Diabetes Research Foundation, Lexicon Pharmaceuticals, MannKind Corporation, Medtronic, Merck & Co., National Institute of Diabetes and Digestive and Kidney Diseases, Novo Nordisk, Roche Diagnostics, Sanofi and T1D Exchange.

Bergenstal reports financial relationships with Abbott Diabetes Care, AstraZeneca, Bayer, Becton, Boehringer Ingelheim Pharmaceuticals, Dexcom, Dickinson and Company, Eli Lilly and Company, Halozyme Therapeutics, Hygieia, Johnson & Johnson, Medtronic, Merck & Co., Novo Nordisk, Roche Diagnostics, Sanofi U.S. and Takeda Pharmaceutical Company Limited.

Securities and Exchange Commission. Lilly undertakes no duty to update forward-looking statements.