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Efficacy and Safety of Liraglutide vs. Placebo When Added to Basal Insulin Analogues in Subjects with Type 2 Diabetes (LIRA-ADD2BASAL): A Randomized, Placebo-Controlled Trial

Canadian Journal of Diabetes, 5, 38, page S7

Aim

To establish superior efficacy and acceptable safety of liraglutide vs. placebo added to pre-existing basal insulin ± metformin in subjects with inadequately controlled type 2 diabetes.

Subjects

Aged 18–80 years, BMI 20–45 kg/m2, A1c 7.0–10.0% and stable insulin dose ≥20 U/day ± stable metformin ≥1500 mg/day. In a multicentre, multi-national, double-blind, parallel-group design, subjects were randomized 1:1 to once daily liraglutide 1.8 mg or placebo for 26 weeks. Insulin adjustments above pre-trial dose were not allowed. Primary endpoint was change in A1c at week 26; 451 subjects were randomized (226 liraglutide; 225 placebo); all but 1 (liraglutide, not exposed) were included in the analysis. Baseline characteristics were similar between groups (liraglutide; placebo): A1c 8.2; 8.3%, BMI 32.3; 32.2 kg/m2, diabetes duration 12.1 years, insulin dose 48.3; 45.9 U (geometric mean 40.5 U for both groups). Subjects taking liraglutide had greater A1c reductions and more reached target using a lower insulin dose vs. placebo (35.8 U vs. 40.0 U). Liraglutide subjects also achieved greater decreases in fasting plasma glucose (FPG), incremental postprandial self-measured plasma glucose (SMPG), body weight, systolic blood pressure (SBP) and lipids. Nausea and vomiting occurred more frequently with liraglutide than placebo (22.2% vs. 3.1% and 8.9% vs. 0.9%, respectively). Minor hypoglycemia occurred in 18.2% and 12.4% of liraglutide and placebo subjects, respectively; no severe hypoglycemia was reported. Addition of liraglutide to basal insulin ± metformin significantly improved glycemia with greater weight loss and reduction in SBP and lipids vs. placebo. Gastrointestinal symptoms and minor hypoglycemia were more frequent with liraglutide than placebo. No severe hypoglycemic events were reported during this trial.

  Liraglutide (n=225) Placebo (n=225) Estimated treatment difference or ratio (liraglutide/placebo) (95% CI) Estimated odds ratio (95% CI) P value
A1c, % a,b –1.30 –0.11 –1.19 (–1.39; –0.99)   <0.0001
Subjects achieving A1c <7% by week 26, % c 59.2 14.0   8.91 (5.45; 14.59) <0.0001
Subjects achieving A1c ≤6.5% by week 26, % c 42.9 3.6   20.12 (9.92; 40.84) <0.0001
Subjects achieving A1c <7% with no weight gain and no hypoglycemia by week 26, % c 41.5 8.6   7.50 (4.36; 12.92) <0.0001
Fasting plasma glucose, mmol/La,b –1.44 –0.16 –1.28 (–1.70; –0.86)   <0.0001
Postprandial increments of 7-point SMPG profile, mmol/L a,b –0.94 –0.37 –0.57 (–0.94; –0.20)   0.0026
Weight, kg a,b –3.54 –0.42 –3.11 (–3.85; –2.37)   <0.0001
Systolic blood pressure, mmHg a,b –5.78 –0.76 –5.02 (–7.45; –2.59)   <0.0001
Pulse, beats/min a,b 3.20 –1.31 4.51 (2.59; 6.43)   <0.0001
Total cholesterol, mmol/L a,d,e 0.92 0.99 0.93 (0.89; 0.96)   0.0002
LDL cholesterol, mmol/L a,d,e 0.90 1.00 0.91 (0.86; 0.96)   0.0013
VLDL cholesterol, mmol/L a,d,e 0.89 0.99 0.91 (0.84; 0.97)   0.0079
HDL cholesterol, mmol/L a,d,e 0.97 0.99 0.98 (0.95; 1.01)   0.1619
Free fatty acids, mmol/L a,d,e 1.02 0.99 1.03 (0.95; 1.12)   0.4491
Triglycerides, mmol/L a,d,e 0.90 0.99 0.90 (0.83; 0.97)   0.0089
Basal insulin analogue dose, U a,d,e 0.87 0.98 0.89 (0.87; 0.92)   <0.0001

aEstimated means and P values from a mixed model for repeated measurements

bValues represent differences from week 0 to week 26

cEstimated proportions and P values from a logistic regression analysis

dValues represent ratios between week 26 to week 0

eLog-transformed prior to analysis

Footnotes

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