Randomised, cOntrolled Multicentre trial of 26 weeks subcutaneous liraglutide (a glucagon-like peptide-1 receptor Agonist), with or without contiNuous positive airway pressure (CPAP), in patients with type 2 diabetes mellitus (T2DM) and obstructive sleep apnoEa (OSA) (ROMANCE): study protocol assessing the effects of weight loss on the apnea-hypnoea index (AHI)

Abstract

Introduction: Obstructive sleep apnoea (OSA) and type 2 diabetes mellitus (T2DM) often occur concurrently, and untreated OSA may potentially amplify the high risk of cardiovascular disease in T2DM. Compliance with continuous positive airway pressure (CPAP), the conventional treatment for OSA, can be poor and considering weight loss is the most effective treatment for OSA. This trial examines whether the glucagon-like peptide-1 receptor agonist liraglutide, a glucose-lowering therapy associated with significant weight loss used in T2DM, can improve the severity and symptoms of OSA.

Methods and analysis: This is an outpatient, single-centred, open-labelled, prospective, phase IV randomised controlled trial in a two-by-two factorial design. One hundred and thirty-two patients with newly diagnosed OSA (apnoea-hypopnoea index (AHI) ≥15 events/hour), and existing obesity and T2DM (glycated haemoglobin (HbA_1c) ≥47 mmol/mol), will be recruited from diabetes and sleep medicine outpatient clinics in primary and secondary care settings across Liverpool. Patients will be allocated equally, using computer-generated random, permuted blocks of unequal sizes, to each of the four treatment arms for 26 weeks: (i) liraglutide (1.8 mg once per day) alone, (ii) liraglutide 1.8 mg once per day with CPAP, (iii) CPAP alone (conventional care) or (iv) no treatment (control). The primary outcome measure is change in OSA severity, determined by AHI. Secondary outcome measures include effects on glycaemic control (glycated haemoglobin (HbA1c)), body weight and quality of life measures. Exploratory measures include measures of physical activity, MRI-derived measures of regional body composition including fat mass (abdominal subcutaneous, visceral, neck and liver fat) and skeletal muscle mass (cross-sectional analysis of thigh), indices of cardiac function (using transthoracic echocardiography) and endothelial function.

Ethical approval: The study has been approved by the North West Liverpool Central Research Ethics Committee (14/NW/1019) and it is being conducted in accordance with the Declaration of Helsinki and Good Clinical Practice.

Trial registration numbers: ISRCTN16250774. EUDRACT No. 2014-000988-41. UTN U1111-1139-0677.

Keywords: diabetes & endocrinology; protocols & guidelines; sleep medicine.

Figure 1

Schematic of protocol. AHI, apnoea–hypopnoea index; BMI, body mass index; CPAP, continuous positive airway pressure; ECHO, echocardiogram; ESS, Epworth Sleepiness Score; FMD, flow-mediated dilatation; HbA1c, glycated haemoglobin; NOX, sleep testing device; ODI, overnight desaturation index; OSA, obstructive sleep apnoea; QoL, quality of life; SAT, subcutaneous adipose tissue; SU, sulphonylureas; T2DM, type 2 diabetes mellitus; VAT, visceral adipose tissue.

Figure 2

MRI (T1-weighted, spin echo, 4 mm slice thickness) showing the mid-sagittal slice of head and neck. Region of interest includes all tissues inferior to hard palate and superior to vocal cords. The following structures to be included in analysis have been highlighted: submental fat, defined as all fat anterior to hyoid and inferior to mandible; tongue (genioglossus); soft palate; airway; lateral parapharyngeal walls; internal neck fat; subcutaneous neck fat.