Second generation basal insulin analogues in clinical trials using continuous monitoring of glucose levels

Summary

Basal 2nd generation insulin analogues are the preferred choice for substituting basal insulin requirements in patients with diabetes mellitus Such insulins are currently insulin Glargine 300U/ml (IGla300) and insulin Degludek 100U/ml (IDeg100). This is due to their longer and more balanced effect and lower risk of hypoglycemia, especially during the night, compared to first-generation basal analogues or NPH insulin. However, clinically significant hypo­glycemia and variability also occur with these insulins and therefore a more detailed assessment of their therapeutic effect is needed than that provided only by the measurement of HbA_1c and glycemic profiles. However the head-to-head comparison of the two basal 2nd generation insulin analogues is limited to two pharmacokinetic studies which evaluated the pharmacokinetics and pharmacodynamics of IGla300 and IDeg100 using a euglyc­emic clamp, with conflicting results, and two RCT head-to-head studies, BRIGHT and CONCLUDE, which compared the efficacy and safety of both insulins based on the evaluation of HbA_1c, SMBG and commonly recorded hypoglycemias, and which have also shown several conflicting results. A more detailed and better picture is provided by an evalu­ation based on continuous monitoring of glucose concentrations according to parameters such as TIR, TBR TAR variability and estimated eHbA_1c. However, only a few monocentric, crossover RCT studies are currently available, which provide such data only in small patient populations and during a short follow-up, and which so far favour the IGla300 to some extent. IGla300 is also favoured by a multicentric, cohort, retrospective RWE study OneCare which assessed the efficacy and safety of IGla300 vs IDeg100 that were evaluated based on CGM data in adult patients with DM1T, who were insufficiently compensated by basal insulin in routine clinical practice. Data from 199 patients were evaluated, while the parameters “Time in range, TIR” (3.9-10.0 mmol/l), “Time above range, TAR” and “Time below range, TBR” were comparable in both cohorts within the whole day (24 hours) evaluation. Similarly, the estimated mean HbA_1c (eHbA_1c) as well as the total insulin dose were comparable in both cohorts. However a difference in the TIR parameter was found in favour of IGla300 during the nighttime (0.00-06.00 h), equal to 52.4% for IGla300, while it was 46,2% for IDeg100, and in the TAR parameter >10.0 mmol/l, when for IGla300 it equalled 40.1%, while for IDeg it was 47.2%. The parameters of glycemic variability (CV, LBGI, HBGI, ADRR, MAGE, MODD) within 24 hours were comparable, but during the nighttime a smoother course of the glycemic curve and lower glycemic oscillations (MAGE) were observed in the IGla300 group as compared to the IDeg100 group. Finally, the number of hyperglycemic episodes was also lower in the IGla300 group (TAR > 10 mmol/l, as well as > 13,9 mmol/l) during the night. Safety parameters from the CGM record, such as the number of hypoglycemic events, and TBR did not differ significantly between the groups, namely for TBR < 3,0 mmol/l and also for TBR < 3,9 mmol/l). There was no difference between the two groups in evaluating satisfaction with the treatment using the DTSQs questionnaire. The limitation of the study is its retrospective character. An even better overview of the comparison could be provided by the head-to-head multicentric, randomized clinical study InRange (NCT04075513). The InRange study will follow 340 participants for 12 weeks. The main monitored parameter will be TIR. The study should be completed in June 2021.

Keywords:

second-generation basal insulin analogs – insulin degludec 100 – insulin glargine 300