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

A Astrup, R Carraro, N Finer, A Harper, M Kunesova, M E J Lean, L Niskanen, M F Rasmussen, A Rissanen, S Rössner, M J Savolainen, L Van Gaal, NN8022-1807 Investigators, Luc Van Gaal, Stepan Svacina, Marie Kunesova, Arne Astrup, Bjørn Richelsen, Kjeld Hermansen, Steen Madsbad, Aila Rissanen, Leo Niskanen, Markku Savolainen, Mazin Al Hakim, Guillem Cuatrecasas Cambra, Belén Sádaba, Raffaele Carraro, Basilio Moreno, Stephan Rössner, Martin Ridderstråle, Michael Lean, Nick Finer, Mike Sampson, A Astrup, R Carraro, N Finer, A Harper, M Kunesova, M E J Lean, L Niskanen, M F Rasmussen, A Rissanen, S Rössner, M J Savolainen, L Van Gaal, NN8022-1807 Investigators, Luc Van Gaal, Stepan Svacina, Marie Kunesova, Arne Astrup, Bjørn Richelsen, Kjeld Hermansen, Steen Madsbad, Aila Rissanen, Leo Niskanen, Markku Savolainen, Mazin Al Hakim, Guillem Cuatrecasas Cambra, Belén Sádaba, Raffaele Carraro, Basilio Moreno, Stephan Rössner, Martin Ridderstråle, Michael Lean, Nick Finer, Mike Sampson

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.

Figures

Figure 1
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
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
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
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.

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