Liraglutide efficacy: Clinical trials
Effective treatment of Type 2 diabetes centres around improvement of glycaemic control and reduction of cardiovascular morbidity and mortality.1
Effective treatment of Type 2 diabetes centres around improvement of glycaemic control and reduction of cardiovascular morbidity and mortality.1
Glycaemic control
The effect of liraglutide on glycaemic control was analysed across five double-blind, randomised, controlled clinical phase 3a trials in 3,978 adult patients.1 Liraglutide treatment produced clinically and statistically significant improvements in glycosylated haemoglobin A1c (HbA1c), fasting plasma glucose and postprandial glucose compared with placebo.1 For further data, see the SmPC.
Cardiovascular morbidity and mortality (LEADER trial)
A large (N=9,340) double-blind cardiovascular outcomes trial, (the ‘LEADER’ trial) was conducted in patients with type 2 diabetes and high cardiovascular risk who were randomly assigned to receive liraglutide (n=4,668) or placebo (n=4,672).1,2 The primary composite outcome in the time-to-event analysis (the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke) occurred in significantly fewer patients in the liraglutide group (608 of 4,668 patients [13.0%]) than in the placebo group (694 of 4,672 [14.9%]) (HR, 0.87; 95%; CI, 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (HR, 0.78; 95%; CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (HR, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were non-significantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events.2
Bioequivalence data
Liraglutide bioequivalence was assessed via a randomized, balanced, open-label, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence trial conducted under fasting conditions. Compared with Victoza® (liraglutide, 6 mg/ml) as the reference product, Zegluxen® (liraglutide, 6 mg/ml) met the bioequivalence criteria in terms of rate and extent of absorption after administration of a single dose (both pre-filled pens) under fasting conditions. For further information on protocols, study design, inclusion criteria, dosing and results, please see below.3
Bioequivalence
Liraglutide bioequivalence was assessed via a randomised, balanced, open-label, two-treatment, two-period, two-sequence, single-dose, crossover bioequivalence trial conducted under fasting conditions.3
The study aimed to demonstrate the bioequivalence of a single 0.6 mg dose of liraglutide 6 mg/mL solution for injection in a pre-filled pen by test product, with Victoza® (reference product), under fasting conditions in healthy adults, and assess safety and tolerability following a single subcutaneous dose of 0.6 mg.3
Results
Compared with Victoza® (liraglutide, 6 mg/ml) as the reference product, Zegluxen® (liraglutide, 6 mg/ml) met the bioequivalence criteria in terms of rate and extent of absorption after administration of a single dose (both pre-filled pens) under fasting conditions.
Table 1: Pharmacokinetic Parameters of liraglutide test and reference formulations under fasting conditions(N=5)6
(SYNCD-24-22) pilot study
| Mean ± SD of liraglutide | ||
| Parameters (Units) | Test (T) | Reference (R) |
| Cmax (ng/ml) | 27.107 ± 4.9506 | 29.380 ± 2.8494 |
| AUC0-t (ng.hr/ml) | 664.020 ± 112.0304 | 726.066 ± 92.0973 |
| AUC 0-inf (ng.hr/ml) | 714.250 ± 110.9486 | 780.626 ± 114.5194 |
| *Tmax (hr) | 12.50 (10,00, 12.50) | 12.00 (12.00, 16.00) |
| Kel | 0.065 ± 0.0108 | 0.068 ± 0.0054 |
| T1/2 | 10.927 ± 2.2349 | 10.239 ± 0.8547 |
| AUC_Extrapolated | 7.17 ± 2.869 | 6.77 ± 2.207 |
| V2/F (ml) | 13694.620 ± 4501.3143 | 11460.336 ± 1071.0841 |
| CL/F (ml/hr) | 855.857 ± 127.7293 | 781.647 ± 111.7651 |
Table 2: Summary of Bioequivalence Study Results Based on Plasma liraglutide Concentrations
Pooled Data for SYNCD-024-22
| Pharmacokinetic parameter | Geometric Least Squares Mean Test (Test, T) | Least Squares Means (Ref, R) | Ratio (T/R) (%) | 90% Confidence Limits (T vs R) | Intra Subject CV % | Power % |
| Ln AUC0-inf
(ng.hr/ml) |
691.0695 | 757.2532 | 91.26 | (81.82, 101.78) | 7.19 | 95.83 |
| Ln AUC0-t
(ng.hr/ml) |
639.5438 | 707.8203 | 90.35 | (82.14, 99.38) | 6.28 | 97.67 |
| Ln (Cmax) (ng/ml) | 26.0545 | 28.8949 | 90.17 | (82.03, 99.11) | 6.23 | 97.74 |
*Median (Minimum, Maximum) values reported for Tmax; SD – Standard Deviation;
(T) Test, a single dose of liraglutide 6 mg/ml solution for injection in pre-filled pen under fasting conditions
(R) Reference; a single dose of Victoza® 6 mg/ml solution for injection in pre-filled pen under fasting conditions
BMI, Body Mass Index; CI, confidence interval; GLP-1 RA, glucagon-like peptide-1 receptor agonist; HR, hazard ratio; HbA1c, haemoglobin A1c; P, probability; SmPC, Summary of Product Characteristics
1. Zegluxen® (liraglutide) Summary of Product Characteristics.
2. Marso SP, Daniels GH, Brown-Frandsen F, et al. B, Nauck, MA. Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes N Engl J Med. 2016 Jul 28; 375(4): 311–322.
3. Liraglutide bioequivalence. Data on File. Zentiva, August 2024.
000697550 | December 2024