Liraglutide 3.0 mg for weight management: weight-loss dependent and independent effects

Abstract

Objective: As an adjunct to a reduced-calorie diet and increased physical activity, treatment with liraglutide 3.0 mg for weight management provides a statistically significant and clinically meaningful weight loss of 5.7%–8.0% compared to 1.6%–2.6% with placebo. The objective of this post hoc analysis was to quantify the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key efficacy endpoints.

Methods: The analysis utilized data from 4725 participants across three randomized, placebo-controlled, double-blind trials that evaluated the efficacy and safety of liraglutide 3.0 mg versus placebo, as an adjunct to a reduced-calorie diet and increased physical activity (ClinicalTrials.gov identifiers: NCT01272219, NCT01272232 and NCT01557166). The duration of two of the trials was 56 weeks; one trial was of 32 weeks’ duration. A mediation analysis was performed, which ranked the relative contribution of weight loss to the treatment effects of liraglutide 3.0 mg on key cardiometabolic efficacy endpoints, Apnea–Hypopnea Index (AHI) and health-related quality of life (QoL). A limitation of this type of analysis is that it cannot conclusively prove a causal relationship.

Results: In individuals without type 2 diabetes mellitus (T2DM), endpoints predominantly driven by liraglutide-induced weight loss included waist circumference, diastolic blood pressure, triglycerides, high density lipoprotein cholesterol, AHI, and Impact of Weight on Quality of Life–Lite total and physical function scores. Endpoints predominantly independent of weight loss included the glycemic endpoints hemoglobin A1c and fasting plasma glucose in individuals with and without T2DM. Regardless of the degree of dependence on weight loss according to the mediation analysis, greater weight loss was associated with greater improvement in all endpoints.

Conclusion: Treatment with liraglutide 3.0 mg contributes to improved cardiometabolic parameters, AHI and health-related QoL through both weight-loss dependent and weight-loss independent mechanisms.

Keywords:

• Antiobesity medications
• GLP-1 receptor agonist
• liraglutide
• obesity therapy
• randomized clinical trial

Note

Transparency

Declaration of funding

All trials supplying data for this analysis were conducted and sponsored by Novo Nordisk (Bagsværd, Denmark). Novo Nordisk performed the statistical analyses and verified the accuracy of the data presented. All authors have significantly contributed to and are in agreement with the content of the manuscript, have approved the final version, and agree to be accountable for all aspects of the work. Full access to the relevant data was available during the preparation of this manuscript.

Declaration of financial/other relationships

H.B. has disclosed that his research site has in the past 12 months received research grants from Amarin, Amgen, Ardea, Arisaph, AstraZeneca, Bristol Meyers Squibb, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Gilead, GSK, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI; in the past 12 months, he has served as a consultant/advisor for Alnylam, Amgen, Eli Lilly, ISIS, Merck, Novartis, Regeneron, Sanofi and Takeda; and a speaker for Amarin, Amgen, AstraZeneca, Eisai, Regeneron, Sanofi and Takeda. X.P. has disclosed that he has received consultant honoraria and research funding support from Novo Nordisk, Johnson and Johnson, Lilly, and Zafgen. J.U.H. has disclosed that she has received consultant honoraria and research grants from Novo Nordisk, and has served as speaker for Novo Nordisk. B.C. and C.B.J. have disclosed that they are employed by and hold stock in Novo Nordisk. L.V.G. has disclosed that he has received grants for clinical research from EU (Hepadip + Resolve consortium); has served as an advisor or consultant for AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly and Company, Janssen Pharmaceuticals Products LP, Johnson & Johnson Pharmaceutical Research & Development LLC, Merck & Co. Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, and Sanofi; has served as a speaker or a member of a speakers bureau for AstraZeneca Pharmaceuticals LP, Boehringer Ingelheim Pharmaceuticals Inc., Eli Lilly and Company, Janssen Pharmaceuticals Products LP, Johnson & Johnson Pharmaceutical Research & Development LLC, Merck & Co. Inc., Novartis Pharmaceuticals Corporation, Novo Nordisk, and Sanofi.

CMRO peer reviewer 1 has disclosed that he has received grants from Amgen, Merck Serono, MSD, AstraZeneca, Novartis, Pfizer and Roche; he is also a consultant to and on the speakers’ bureau of Amgen AstraZeneca, Merck Serono and Sanofi. Peer reviewer 2 has no relevant financial or other relationships to disclose.

Acknowledgments

The authors thank Peter Brøndum Jacobsen MD PhD (Novo Nordisk) for contributing to the manuscript reviews. Medical writing support and submission assistance was provided by Lillian Jespersen MSc and Angela Stocks PhD, Larix A/S (Copenhagen, Denmark) and supported by Novo Nordisk.

Previous presentation: The results contained in this manuscript were previously presented at the Endocrine Society’s 97th Annual Meeting and Expo, March 2015 (Bays et al. Liraglutide 3.0 mg: weight-loss dependent and independent effects. Endocrine Rev 2015;36 [Suppl 1]:Abstract 551) and the 22nd European Congress of Obesity, May 2015 (Van Gaal et al. Liraglutide 3.0 mg: weight-loss dependent and independent effects. Obesity Facts 2015;8[Suppl 1]:41 [Abstract T8.0S2.1]).

Notes

1 Saxenda is a registered trade name of Novo Nordisk A/S, Bagsværd, Denmark