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PK/PD of Glargine-300units/ml Compared to Degludec-100units/ml

Jan 23, 2021
 
Editor: Steve Freed, R.PH., CDE

Author: Abdullah Al-Ajmi, PharmD Candidate, Skaggs School of Pharmacy and Pharmaceutical Sciences

Glargine and degludec had similar glycemic control with some differences in pharmacokinetics (PK) and pharmacodynamics (PD). 

Long-acting basal insulin analogues glargine 300units/ml (Glargine-300) and degludec 100-200units/ml (Degludec-100 and Degludec-200) have lower hypoglycemia risks in patients with type 1 diabetes (T1D) when compared to 1st generation basal analogues such as glargine 100units/ml (Glargine-100) all while providing the same blood glucose control. The differences in pharmacokinetics (PK) and pharmacodynamics (PD) between Glargine-300 and Degludec-100 have shown debatable outcomes. Some studies looked at the PK/PD effect of Glargine-300 and Degludec-(100 and 200). The results showed that when administering the same dose, Glargine-300 produced around 30% less effect compared to Degludec-200. Another showed that Glargine-300 had less steady variability compared to Degludec-100. Patients use lower doses with Degludec compared to Glargine-300 in clinical practice. This study aims to determine the PK/PD differences between Glargine-300 and Degludec-100. 

 

The study was a randomized, cross-over trial single-blinded design. Participants were randomized to receive either Glargine-300 or Degludec-100. Patients included had to be diagnosed with T1D for at least five years. They also had to be 18-65 years old with an A1C between 6.5-8.5% and a BMI from 20-27kg/m2. The patients had to be naive to Glargine and Degludec and not complaining of microvascular and macrovascular complications. Basal insulin was titrated two times per week based on self-monitoring of plasma glucose. 

The primary endpoint was defined as the area under the curve (AUC) from the glucose infusion rate (GIR) by time 0-24 hours. Secondary endpoints were defined as GIR-AUC 0-6 hours, 6-12 hours, 12-18 hours, 18-24 hours, 0-12 hours, and 12-24 hours. Also, maximum GIR, changes in GIR, and time to 50% GIR-AUC 0-24 hours. Also, insulin-AUC 0-24 hours, 0-12 hours, 12-24 hours, 0-6 hours, 6-12 hours,12-18 hours, 18-24 hours and time to 50% insulin-AUC (0-24 hours). Other endpoints included parameters like glucose utilization, glucagon, endogenous glucose production, b-hydroxybutyrate, glycerol, alanine, free fatty acids, and lactate. 

The results showed that patients had similar body weight and A1C after three months of treatment. The dose reported to be higher in the Glargine-300 group (0.34±0.08units/kg); compared to Degludec-100 (0.26±0.06units/kg); with a 0.084units/kg difference which was clinically significant 95% confidence interval (CI) 0.-0.097. In terms of prandial insulin dose, similar results were seen as glargine had higher doses with an average difference of 0.038units/kg. Hypoglycemia was not reported. 

The results showed that glargine-300 started with 15.5±5.2µU/ml at T0 and it reached a peak of 22.2±8.7 µU/ml after around 5hours. On the other hand, degludec-100 started with 393±109µU/ml at T0 then peaked with a concentration of 567±149µU/ml after 7 hours. It shows that Gla-300 produced lower insulin concentration compared to degludec. The levels dropped to the baseline level at the end of the study. However, there was no statistical difference in the GIR between the groups at T0. Glargine-300 average GIR was 0.54±0.31mg/kg/min; compared to degludec-100 GIR which was 0.68±0.58mg/kg/min with an average difference of 0.14 (95% CI, -0.48 to 0.18). The GIR results showed that at T6, glargine-300 had a 15% higher GIR then returned to a similar range. The same thing was reported during the last 6 hours of the study. Glargine had a 12% lower GIR compared to degludec. Moreover, similar GIR results were reported at T0 and T24. Glargine was associated with lower overall fluctuations (20%) than degludec’s (23%). The average blood glucose level was similar between the groups with a nonsignificant difference of 0.36 (95% CI, -1.5 to 2.6).    

In terms of glucose utilization and endogenous glucose production (EGP), both drugs had a similar EGP at T0 with a nonsignificant difference of 0.16 (95% CI, -0.24 to 0.57, P=0.411). Both drugs had a similar total EGP suppression between T0 to T24. However, the EGP suppression profile was different in T0-T6 and T18-T24, in which glargine had suppression by 24% compared to degludec, which was around 20%. In contrast, degludec produced higher EGP suppression between T12 to T18.   

The doses of glargine-300 and degludec-100 produced similar insulin therapeutic effect. Some of the study limitations include that the difference in PK/PD in day-to-day activity was not measured. Moreover, the study looked at the insulin when doses were administered at night; this may not reflect on morning dose administration. Further studies may be considered to address the limitations of this study. 

Practice Pearls: 

  • Similar PD outcomes were reported with glargine 300units and degludec 100units. 
  • Both insulins produced stable concentration, but degludec had higher peaks. 
  • Both insulins produced a similar total EGP over 24hours. 

  

Lucidi, Paola et al. “Pharmacokinetic And Pharmacodynamic Head-To-Head Comparison Of Clinical, Equivalent Doses Of Insulin Glargine 300 Units/Ml And Insulin Degludec 100 Units/Ml In Type 1 Diabetes”. Diabetes Care, 2020, p. dc201033. American Diabetes Association, doi:10.2337/dc20-1033. Accessed 1 Dec 2020. Available from: https://care.diabetesjournals.org/content/early/2020/11/09/dc20-1033 

  

Heise, Tim et al. “Insulin degludec: Lower day-to-day and within-day variability in pharmacodynamic response compared with insulin glargine 300 U/mL in type 1 diabetes.” Diabetes, obesity & metabolism vol. 19,7 (2017): 1032-1039. doi:10.1111/dom.12938 Available from: https://dom-pubs.onlinelibrary.wiley.com/doi/full/10.1111/dom.12938 

  

Bailey, T S et al. “Morning administration of 0.4U/kg/day insulin glargine 300U/mL provides less fluctuating 24-hour pharmacodynamics and more even pharmacokinetic profiles compared with insulin degludec 100U/mL in type 1 diabetes.” Diabetes & metabolism vol. 44,1 (2018): 15-21. doi:10.1016/j.diabet.2017.10.001. Available from: https://www.sciencedirect.com/science/article/pii/S1262363617305384?via%3Dihub 

  

Abdullah Al-Ajmi, PharmD Candidate, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences    

 

 

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