Liraglutide and the Preservation of Pancreatic β-Cell Function in Early Type 2 Diabetes: The LIBRA Trial Featured Article: Ravi Retnakaran, Caroline K. Kramer, Haysook Choi, Balakumar Swaminathan, and Bernard Zinman Diabetes Care Volume 37: 3270-3278 December, 2014

STUDY OBJECTIVE   Study determined whether liraglutide can preserve -cell function over 48 weeks in early type 2 diabetes (T2DM) after initial elimination of glucotoxicity with intensive insulin therapy (IIT) Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

STUDY DESIGN AND METHODS Study was a double-blind, randomized, placebo-controlled trial with 51 patients with T2DM of 2.6 ± 1.9 years’ duration and an A1C of 6.8 ± 0.8% Subjects completed 4 weeks of IIT before randomization to daily subcutaneous liraglutide or placebo injection Serial assessment of -cell function was performed with an Insulin Secretion-Sensitivity Index-2 (ISSI-2) on oral glucose tolerance test every 12 weeks Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

Data are %; mean 6 SD, if normally distributed; or median (25th–75th), if skewed. Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

Data are mean 6 SE or %. P for linear trend Data are mean 6 SE or %. *P for linear trend. §Data are geometric mean (95% CI). Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

RESULTS Primary outcome of baseline-adjusted ISSI-2 at 48 weeks was higher in the liraglutide group than in the placebo group Baseline-adjusted HbA1c at 48 weeks was lower in the liraglutide group At each quarterly assessment, >50% of participants on liraglutide had an HbA1c ≤6.0% and glucose tolerance in the nondiabetic range No difference was found in the incidence of hypoglycemia between the liraglutide and placebo groups Two weeks after stopping treatment, the beneficial effect on ISSI-2 of liraglutide versus placebo was entirely lost Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

Figure 1—Changes over time in b-cell function, measured by ISSI-2 (A), DIns0–120/Dgluc01203Matsuda index (B); DCpep0–120/Dgluc0–1203Matsuda index (C); and DISR0–120/Dgluc0–120 3 Matsuda index (D). P values are for interaction between treatment group and time during the intervention. Due to single negative or missing values precluding use of the index, the respective sample sizes analyzed in the placebo and liraglutide groups in B–D were as follows: 24 and 21 for DIns0–120/Dgluc0–120 3 Matsuda index; 24 and 23 for DCpep0–120/Dgluc0–120 3 Matsuda index; and 24 and 23 for DISR0–120/Dgluc0–120 3 Matsuda index. Pre-IIT, before IIT; Rand, randomization visit. Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

Figure 2—Changes over time in HbA1c (A), Matsuda index of insulin sensitivity (B), BMI (C), and waist circumference (D). P values are for interaction between treatment group and time during the intervention. Pre-IIT, before IIT; Rand, randomization visit. Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

CONCLUSIONS Liraglutide provides robust enhancement of -cell function that is sustained over 48 weeks in early T2DM but lost on cessation of therapy Retnakaran R. et al. Diabetes Care 2014;37:3270-3278

Figure 3—Proportion of participants in each treatment group with HbA1c,6.5% (,48 mmol/mol) (A), HbA1c #6.0% (#42 mmol/mol) (B), and glucose tolerance status in the nondiabetic range on OGTT (C). *P , 0.05 for comparison between groups. Rand, randomization visit. Retnakaran R. et al. Diabetes Care 2014;37:3270-3278