Effect of liraglutide 3.0 mg in individuals with obesity and moderate or severe obstructive sleep apnea: the SCALE Sleep Apnea randomized clinical trial

Abstract

Background: Obesity is strongly associated with prevalence of obstructive sleep apnea (OSA), and weight loss has been shown to reduce disease severity.

Objective: To investigate whether liraglutide 3.0 mg reduces OSA severity compared with placebo using the primary end point of change in apnea-hypopnea index (AHI) after 32 weeks. Liraglutide's weight loss efficacy was also examined.

Subjects/methods: In this randomized, double-blind trial, non-diabetic participants with obesity who had moderate (AHI 15-29.9 events h(-1)) or severe (AHI ⩾30 events h(-1)) OSA and were unwilling/unable to use continuous positive airway pressure therapy were randomized for 32 weeks to liraglutide 3.0 mg (n=180) or placebo (n=179), both as adjunct to diet (500 kcal day(-1) deficit) and exercise. Baseline characteristics were similar between groups (mean age 48.5 years, males 71.9%, AHI 49.2 events h(-1), severe OSA 67.1%, body weight 117.6 kg, body mass index 39.1 kg m(-2), prediabetes 63.2%, HbA1c 5.7%).

Results: After 32 weeks, the mean reduction in AHI was greater with liraglutide than with placebo (-12.2 vs -6.1 events h(-1), estimated treatment difference: -6.1 events h(-1) (95% confidence interval (CI), -11.0 to -1.2), P=0.0150). Liraglutide produced greater mean percentage weight loss compared with placebo (-5.7% vs -1.6%, estimated treatment difference: -4.2% (95% CI, -5.2 to -3.1%), P<0.0001). A statistically significant association between the degree of weight loss and improvement in OSA end points (P<0.01, all) was demonstrated post hoc. Greater reductions in glycated hemoglobin (HbA1c) and systolic blood pressure (SBP) were seen with liraglutide versus placebo (both P<0.001). The safety profile of liraglutide 3.0 mg was similar to that seen with doses ⩽1.8 mg.

Conclusions: As an adjunct to diet and exercise, liraglutide 3.0 mg was generally well tolerated and produced significantly greater reductions than placebo in AHI, body weight, SBP and HbA1c in participants with obesity and moderate/severe OSA. The results confirm that weight loss improves OSA-related parameters.

Trial registration: ClinicalTrials.gov NCT01557166.

Conflict of interest statement

Dr Blackman: consultant/advisory board participant for Novo Nordisk, Merck Canada, Valeant Canada, Paladin Labs Inc. Dr Foster: at the time of the study was a scientific advisory board participant for Con Agra Foods, United Health Group and Tate and Lyle, and a consultant to Eisai and Novo Nordisk; currently employed by Weight Watchers International. Dr Zammit: consultant for Acorda, Actelion, Alexza, Arena, Aventis, Biovail, Boehringer-Ingelheim, Cephalon, Elan, Eli Lilly, Evotec, Forest, Glaxo Smith Kline, Jazz, King Pharmaceuticals, Ligand, McNeil, Merck, Neurocrine Biosciences, Organon, Pfizer, Purdue, Renovis, Sanofi-Aventis, Select Comfort, Sepracor, Shire, Somnus, Takeda Pharmaceuticals, Vela, Wyeth; grants/research support from Abbott, Abbvie, Actelion, Ancile, Apnex, Arena, Astra-Zeneca, Aventis, Banyu, Biomarin, BMS, Catalyst, Cephalon Inc., CHDI, Elan, Epix, Eisai, Elminda, Evotec, Forest, Galderma, Genentech, Gilead, Glaxo Smith Kline, Gilead, H. Lundbeck A/S, Janssen, Johnson & Johnson, King, Merck and Co., National Institute of Health (NIH), Neurim, Neurocrine Biosciences, Naurex, Neurim, Neurogen, Novo Nordisk, Organon, Orphan Medical, Otsuka, Pfizer, Predix, Respironics, Saladax, Sanofi-Aventis, Sanofi-Synthelabo, Schering-Plough, Sepracor, Sunovion, Shire, Somaxon, Takeda Pharmaceuticals North America, Targacept, Teva, Thymon, Transcept, UCB Pharma, Ultragenyx, Predix, Vanda, Wyeth-Ayerst Research; honoraria received from Neurocrine Biosciences, King Pharmaceuticals, McNeil, Sanofi-Aventis, Sanofi-Synthelabo, Sepracor, Takeda Pharmaceuticals, Vela Pharmaceuticals, Wyeth-Ayerst Research; ownership interest in Clinilabs, Inc., Clinilabs IPA, Inc., Home Sleep and Respiratory Care, Nationwide Sleep Testing. Dr Rosenberg: received research grant support from Merck, Novo Nordisk, Pfizer, Teva, Jazz Pharmaceuticals, Sunovion Pharmaceuticals and Philips-Respironics. Dr Aronne: advisory board member for Myos Corporation; consultant, speaker, advisor, or received research support from Aspire Bariatrics Inc., Eisai, Ethicon Endo-Surgery Inc., GlaxoSmithKline Consumer Healthcare LP, GI Dynamics, Novo Nordisk, Pfizer, Takeda Pharmaceuticals, Vivus Inc., Zafgen Inc.; ownership interest in Myos Corporation and BMIQ. Dr Wadden: advisory board participant for Orexigen Pharmaceuticals, Inc., Novo Nordisk, Nutrisystem, and Shire Pharmaceuticals, with research support (to the University of Pennsylvania) from the first three companies. Dr Claudius: employee of Novo Nordisk and owns company stock. Dr Jensen: employee of Novo Nordisk and owns company stock. Dr Mignot: advisory board member, consultant for and research support from Jazz Pharmaceuticals; consultant for and research grant from Novo Nordisk; consultant for Reset Pharmaceuticals and Merck; expert witness for FTC.

Figures

Figure 1

Trial design. EOT, end of treatment; FU, follow-up.

Figure 2

Trial flow. Participants could be ineligible for trial enrollment because of more than one inclusion/exclusion criterion. *Participants did not receive any trial drug and withdrew from the trial. **Non-compliance with the trial protocol included, but was not limited to, incorrect handling of trial product, non-compliance to visit schedule and dietary advice and non-completion of trial-related questionnaires.

Figure 3

Change in AHI and body weight over 32 weeks of treatment and the relationship between weight loss and change in AHI. (a) Change in AHI during the treatment period. (b) Change in body weight during the treatment period. (c) Relationship between weight loss and change in AHI. (a, b) Data are observed means±s.e. from the full analysis set (FAS). The last observation carried forward (LOCF) value is shown at week 32. In c, data are mean±s.e. from the FAS, LOCF. Weight gain or loss category represents the change in body weight (%) from baseline after 32 weeks of treatment. PSG assessments were performed at weeks –1 (baseline), 12 and 32. For PSG-derived parameters (that is, AHI), participants without any post-baseline PSG assessments were excluded from the analyses. For the body weight parameter, participants without any post-baseline measurements were excluded from the analyses; in addition, participants without baseline measurements were excluded from the change from baseline analyses. N, number of participants; n, number of participants in each weight loss category; WG, weight gain; WL, weight loss.

Figure 4

Changes in PSG, quality of life and cardiometabolic end points after 32 weeks of treatment. (a) Changes in PSG and quality of life end points. (b) Changes in cardiometabolic end points. Forest plots show estimated treatment differences (ETDs)/odds ratios and 95% CIs. Data are from the full analysis set (last observation carried forward (LOCF)). Data at baseline are mean±s.d. For PSG-derived parameters, participants without any post-baseline PSG assessments were excluded from the analyses. For quality of life and cardiometabolic parameters, participants without any post-baseline measurements were excluded from the analyses; in addition, participants without baseline measurements were excluded from the change from baseline analyses. Improvement/worsening refer to the changes from baseline with liraglutide 3.0 mg relative to those with placebo. DBP, diastolic blood pressure; ESS, Epworth Sleepiness Scale; FPG, fasting plasma glucose; I, improvement; ODI, oxygen desaturation index; SpO2, oxygen saturation; WASO, wake time after sleep onset.