Basal insulin peglispro, lacking peripheral action, was compared to insulin glargine in a 52-week trial in type 2 diabetic patients previously treated with basal insulin.
One of the main reasons diabetic patients fail to control their blood glucose with insulin and other oral antidiabetic medications (OAMs) is due to fear of hypoglycemia and weight gain. Hypoglycemia is one of the limiting factors in titrating basal insulin doses in diabetic patients with uncontrolled blood glucose.
Basal insulin peglispro (BIL) is a PEGylated insulin lispro. It has a half-life of 2-3 days and has duration of action related to delayed insulin absorption and reduced clearance. BIL’s actions on the liver is said to be beneficial in type 1 diabetic patients, due to its lesser peripheral action rather than accentuated effect on the liver. A previous trial conducted by Bergenstal RM et al., was a 12-week phase 2 trial that compared BIL with glargine in patients with type 2 diabetes previously treated with basal insulin. In the trial, BIL was associated with similar glycemic control as glargine, lower nocturnal hypoglycemia and weight gain, and an increase in triglyceride and aminotransferases.
This 52-week phase 3 open-label study compared the safety and efficacy of switching to BIL in patients with type 2 diabetes previously treated with basal insulin or a combination of three or less OAMs. This was a phase 3, open-labeled, multicenter multinational, randomized controlled, parallel-design trial. Investigators in 65 centers in 8 different countries participated in the trial. In order to eliminate any bias of this open-labeled study, the sponsor study team, the overseeing physician, and the statistician were initially blinded until primary database lock at 26 weeks. The inclusion criteria were adults with type 2 diabetes treated with basal insulin (glargine, detemir, or NPH insulin) or three of fewer OAM for > 90 days and had an HbA1c < 9%, BMI > 45 kg/m2, and women with a negative pregnancy test who do not plan to get pregnant during the trial.
466 patients were randomized to BIL (n=307) or glargine (n=159). The primary objective of determining non-inferiority of BIL to glargine was HbA1c change from 0 to 26 weeks, which was achieved with least square mean of -0.52% (95% CI -0.67 to -0.38, P<0.001) indicating BIL was statistically superior. HbA1c reduction was superior in BIL compared to glargine (-0.82% vs-0.29%, 95% CI -7.3 to -4.2, P<0.001). More patients treated with BIL achieved HbA1c <7% at weeks 26 (72.5% vs. 52.2%) and 52 (63.9% vs. 45.9%). BIL patients achieved HbA1c <7 and 6.5% without nocturnal hypoglycemia more than glargine patients (P<0.001). Total hypoglycemia rates were less in BIL-treated patients at week 52 (P<0.001). In addition, fasting serum glucose (FSG) was less for BIL-treated patients at weeks 26 and 52. Triglyceride, aminotransferases, and liver fat content (LFC) were increased in BIL-treated patients at weeks 26 and 52 (P<0.05 and P<0.001, respectively).
This study, in patients with type 2 diabetes previously treated with basal insulin, demonstrated that switching to BIL proves beneficial for glycemic control with significant reductions in HbA1c, nocturnal hypoglycemia, and lower glucose variability. As aforementioned, one of the limiting factors in maintaining glucose control is the risk of hypoglycemia when titrating insulin doses. BIL-treated patients in this trial had significantly less total and nocturnal hypoglycemia (60% reduction), eliminating the limiting factor. Although BIL-treated patients achieved lower HbA1c levels, weight gain was not significantly different between BIL and glargine-treated patients.
Aminotransferases was observed to increase in BIL-treated patients. However, no cases were associated with an increase in bilirubin. Hence eliminating future risk of drug-induced liver injury. Commonly, insulin decreases LFC in insulin-naïve type 2 diabetic patients by decreasing fatty acid delivery to the liver by increasing fat delivery to the peripheral tissues through increases lipolysis in the adipose tissue. In this study, glargine-treated patients did not experience LFC increase due their LFC already being increased from prior treatment with basal insulin. Switching from conventional insulin to BIL (less peripheral action) could have increased the LFC due to decreased suppression of lipolysis in BIL-treated patients.
- Basal insulin peglispro is a PEGylated insulin lispro that has lesser peripheral action compared to basal insulin, therefore contributing to its hepato-preferential actions.
- BIL was shown to be superior to insulin glargine in HbA1c reduction, nocturnal hypoglycemia, and glucose variability in 26 and 52 weeks.
- BIL-treated patients had higher aminotransferases, LFC, and triglycerides as compared to glargine-treated patients at 26 and 52 weeks. However, this could be due to the conversion from conventional basal insulin to BIL, insulin with reduced peripheral action.
Buse JB, Rodbard HW, Trescoli Serrano C, et al. Randomized Clinical Trial Comparing Basal Insulin Peglispro and Insulin Glargine in Patients With Type 2 Diabetes Previously Treated With Basal Insulin: IMAGINE 5. Diabetes Care. 2016;39(1):92-100.
Researched and prepared by Sabair Pradhan, Doctor of Pharmacy Candidate USF College of Pharmacy, reviewed by Dave Joffe, BSPharm, CDE