Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide

Abstract

Objective: Having demonstrated short-term weight loss with liraglutide in this group of obese adults, we now evaluate safety/tolerability (primary outcome) and long-term efficacy for sustaining weight loss (secondary outcome) over 2 years.

Design: A randomized, double-blind, placebo-controlled 20-week study with 2-year extension (sponsor unblinded at 20 weeks, participants/investigators at 1 year) in 19 European clinical research centers.

Subjects: A total of 564 adults (n=90-98 per group; body mass index 30-40 kg m(-2)) enrolled, 398 entered the extension and 268 completed the 2-year trial. Participants received diet (500 kcal deficit per day) and exercise counseling during 2-week run-in, before being randomly assigned (with a telephone or web-based system) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg, n=90-95), placebo (n=98) or open-label orlistat (120 mg × 3, n=95). After 1 year, liraglutide/placebo recipients switched to liraglutide 2.4 mg, then 3.0 mg (based on 20-week and 1-year results, respectively). The trial ran from January 2007-April 2009 and is registered with Clinicaltrials.gov, number NCT00480909.

Results: From randomization to year 1, liraglutide 3.0 mg recipients lost 5.8 kg (95% confidence interval 3.7-8.0) more weight than those on placebo and 3.8 kg (1.6-6.0) more than those on orlistat (P0.0001; intention-to-treat, last-observation-carried-forward). At year 2, participants on liraglutide 2.4/3.0 mg for the full 2 years (pooled group, n=184) lost 3.0 kg (1.3-4.7) more weight than those on orlistat (n=95; P<0.001). Completers on liraglutide 2.4/3.0 mg (n=92) maintained a 2-year weight loss of 7.8 kg from screening. With liraglutide 3.0 mg, 20-week body fat decreased by 15.4% and lean tissue by 2.0%. The most frequent drug-related side effects were mild to moderate, transient nausea and vomiting. With liraglutide 2.4/3.0 mg, the 2-year prevalence of prediabetes and metabolic syndrome decreased by 52 and 59%, with improvements in blood pressure and lipids.

Conclusion: Liraglutide is well tolerated, sustains weight loss over 2 years and improves cardiovascular risk factors.

Figure 1

Study design. ^*From 20–52 weeks, participants/investigators remained blinded to liraglutide/placebo treatment but the sponsor was unblinded; after 1 year, all were unblinded.

Figure 2

(a) Mean changes in body weight and waist circumference from randomization to years 1 and 2. (b) Participants with >5 and >10% randomization weight loss at years 1 and 2. (c) Mean changes in BP and pulse rate from randomization to years 1 and 2. Estimated mean changes in weight, waist, BP and pulse rate (by ANCOVA), and in weight-loss responders (by logistic regression) are shown for the intention-to-treat population with the last observation carried forward.

Figure 3

(a) Change in body weight from screening over 2 years, presented as observed data for individuals completing each scheduled visit. (b) Estimated (ANCOVA) changes in BP and pulse rate from screening to year 2 for the completer population. (c) Mean change in pulse rate over 2 years, presented as observed data for the intention-to-treat population (with no imputation).

Figure 4

(a) The prevalence of prediabetes and the metabolic syndrome at randomization and after 1 and 2 years of treatment. Metabolic syndrome is defined by updated NCEP-ATP III criteria. (b) Mean changes in lipids from randomization to years 1 and 2. Estimated (ANCOVA) changes are shown for the intention-to-treat population with the last observation carried forward.