Tolerability of nausea and vomiting and associations with weight loss in a randomized trial of liraglutide in obese, non-diabetic adults

Abstract

Background: Liraglutide 3.0 mg, with diet and exercise, produced substantial weight loss over 1 year that was sustained over 2 years in obese non-diabetic adults. Nausea was the most frequent side effect.

Objective: To evaluate routinely collected data on nausea and vomiting among individuals on liraglutide and their influence on tolerability and body weight.

Design: A randomized, placebo-controlled, double-blind 20-week study with an 84-week extension (sponsor unblinded at 20 weeks, open-label after 1 year) in eight European countries (Clinicaltrials.gov: NCT00422058).

Subjects: After commencing a 500-kcal/day deficit diet plus exercise, 564 participants (18-65 years, body mass index (BMI) 30-40 kg m(-2)) were randomly assigned (after a 2-week run-in period) to once-daily subcutaneous liraglutide (1.2, 1.8, 2.4 or 3.0 mg), placebo or open-label orlistat (120 mg × 3 per day). After 1 year, participants on liraglutide/placebo switched to liraglutide 2.4 mg, and subsequently, to liraglutide 3.0 mg (based on 20-week and 1-year results, respectively).

Results: The intention-to-treat population comprised 561 participants (n=90-98 per arm, age 45.9±10.3 years, BMI 34.8±2.7 kg m(-2) (mean±s.d.)). In year 1, more participants reported ⩾1 episode of nausea/vomiting on treatment with liraglutide 1.2-3.0 mg (17-38%) than with placebo or orlistat (both 4%, P⩽0.001). Most episodes occurred during dose escalation (weeks 1-6), with 'mild' or 'moderate' symptoms. Among participants on liraglutide 3.0 mg, 48% reported some nausea and 13% some vomiting, with considerable variation between countries, but only 4 out of 93 (4%) reported withdrawals. The mean 1-year weight loss on treatment with liraglutide 3.0 mg from randomization was 9.2 kg for participants reporting nausea/vomiting episodes, versus 6.3 kg for those with none (a treatment difference of 2.9 kg (95% confidence interval 0.5-5.3); P=0.02). Both weight losses were significantly greater than the respective weight losses for participants on placebo (P<0.001) or orlistat (P<0.05). Quality-of-life scores at 20 weeks improved similarly with or without nausea/vomiting on treatment with liraglutide 3.0 mg.

Conclusion: Transient nausea and vomiting on treatment with liraglutide 3.0 mg was associated with greater weight loss, although symptoms appeared tolerable and did not attenuate quality-of-life improvements. Improved data collection methods on nausea are warranted.

Figures

Figure 1

Study design. *During 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) The proportion of individuals reporting nausea/vomiting at any time during year 1 (logistic regression analysis). Data are estimated means. Odds ratios (OR) versus placebo/orlistat are shown, together with 95% CI. The proportion of participants reporting nausea (b) and vomiting (c) by country in year 1. (d) Severity of nausea and vomiting episodes reported in year 1. (e) The proportion of individuals with nausea at any time during 2 years of treatment, by week. Safety analysis set.

Figure 3

Weight change at year 1 (a) and year 2 (b) in individuals with or without at least one episode of nausea or vomiting. Mean changes (analysis of covariance) are shown for the intention-to-treat population with the last observation carried forward. Estimated treatment differences (ETD) are shown, together with 95% CI.

Figure 4

Mean (analysis of covariance) changes (positive=improved) in quality-of-life scores (IWQoL-Lite) among individuals on liraglutide 3.0 mg at 20 weeks, in individuals with or without at least one episode of nausea or vomiting (intention-to-treat population with the last observation carried forward). IWQoL-Lite scores ranged from 0 (worst) to 100 (best).