Short summary

This study aims to investigate the prevalence of obstructive sleep apnea (OSA) in patients with type 2 diabetes (T2D) and the potential effectiveness of mandibular advancement device (MAD) treatment. The study involves screening T2D patients for OSA using questionnaires and monitoring. Up to 35 patients will be referred for MAD treatment. The study evaluates outcomes such as normalized AHI, reduced daytime fatigue, lowered blood pressure, and treatment adherence.

Rationale

Obstructive sleep apnea (OSA) is characterized by periodic cessation of breathing for 10 seconds or longer during sleep. In patients with type 2 diabetes (T2D), OSA is frequently occurring and likely underdiagnosed [1, 2]. In addition to abnormal daytime tiredness and decreased cognition [3], OSA is also associated with an increased incidence of cardiovascular disease [4-8], kidney insufficiency [9], cancer [10, 11], and increased mortality (both cardiovascular and general mortality) [5, 12].

The diagnosis of OSA is established through Cardio-Respiratory Monitoring (CRM), and its severity is defined by the number of apnea/hypopnea (AHI) episodes per hour:

AHI < 5/hour: No sleep apnea AHI 5-14/hour: Mild sleep apnea AHI 15-29/hour: Moderate sleep apnea AHI > 30/hour: Severe sleep apnea

In a Danish screening study conducted at the Steno Diabetes Center in Gentofte (2014), it was found that 39% of referred patients with T2D had symptomatic OSA, with a distribution of severity being mild (44%), moderate (30%), and severe OSA (26%) [13]. In 2020 and 2021, a total of 27 patients were referred from SDCO to the pulmonary outpatient clinic in Svendborg, which handles OSA screening and treatment. This indicates that there is currently significant underdiagnosis of OSA at the Steno Diabetes Center Odense (SDCO).

Continuous positive airway pressure (CPAP) is currently the primary treatment for moderate to severe OSA, while treatment with a dental appliance called a mandibular advancement device (MAD) is only used for mild to moderate OSA. CPAP treatment is funded as a regional treatment option, whereas MAD treatment is self-funded by patients (up to 15,000 DKK through private practicing dentists).

In general, the effectiveness of CPAP treatment for OSA has been more thoroughly studied compared to the effectiveness of MAD. The main differences and similarities between CPAP and MAD treatment, regarding treatment adherence and effectiveness, can be summarized as:

Symptomatic patients with moderate to severe OSA generally have high treatment adherence to CPAP treatment, while those with mild to moderate OSA and few symptoms have low adherence to treatment. MAD treatment is generally well tolerated by patients, with overall higher treatment adherence compared to CPAP [14]. Both CPAP and MAD treatments reduce AHI episodes, with CPAP having a greater effect [15]. Both CPAP and MAD treatments have comparable effects on patient-centered outcomes such as improvement in fatigue and quality of life [14]. CPAP and MAD treatments are equivalent in terms of blood pressure reduction, with a modest effect of approximately 2-3 mmHg (systolic) and 1-2 mmHg (diastolic) [15-18]. However, significantly greater effects are observed in patients with high blood pressure before initiating therapy [19]. Randomized and placebo-controlled studies have demonstrated a positive effect of MAD treatment in patients with severe OSA (AHI > 30/hour) [20, 21]. Treatment with MAD in patients with T2D is not well-studied. In a smaller Danish study from the maxillofacial department at Odense University Hospital (OUH), it was found that MAD treatment had a positive effect on AHI, fatigue, and blood pressure. Furthermore, this effect was independent of the severity of OSA and the presence of T2D (Marcussen et al, 2015, unpublished).

Reasons for referrals for MAD treatment at OUH have recently been compiled: 3/4 are referred due to lack of cooperation or side effects with CPAP treatment, while 1/4 of the referrals are due to lack of effectiveness of CPAP treatment and/or with the aim of reducing CPAP pressure. Among the referred patients, there is a good effect of MAD treatment assessed by reduction in AHI, ∆AHI/hour ≈ 20, either as solo therapy (≈ 90% of treated) or dual therapy - combined with CPAP (≈ 10%).

Purpose The purpose of the pilot study is to investigate the basis for systematic screening for obstructive sleep apnea (OSA) in individuals with type 2 diabetes (T2D) at SDCO (Steno Diabetes Center Odense). Additionally, it aims to examine the foundation for an intervention study that includes treatment with a mandibular advancement device (MAD). The study is expected to uncover the prevalence of individuals requiring screening through Cardio-Respiratory Monitoring (CRM), the prevalence of individuals potentially needing treatment, and the occurrence of individuals for whom MAD treatment is feasible. Furthermore, the study aims to assess the resource utilization associated with screening and MAD treatment.

Hypothesis Between 25% and 35% of T2D patients attending the same-day screening (SDK) at SDCO are undiagnosed with sleep apnea and could potentially benefit from treatment. The effectiveness of treatment will be clinically reflected in lower nighttime blood pressure, reduced HbA1c levels, and improved quality of life.

Description of the cohort

All patients with T2D attending the SDK at SDCO during the period from July 2023 to July 2024 will be offered the opportunity to participate in the study. A total of 100 patients will be screened for obstructive sleep apnea (OSA) using questionnaires, specifically the Berlin Questionnaire (BerlinQ) and the Epworth Sleepiness Scale (ESS). Patients who are unable to complete a questionnaire in Danish will be offered assistance from an interpreter or a student assistant/nurse to fill out the questionnaire if it's not available in their language. Out of the 100 screened individuals, we anticipate being able to refer up to 35 patients for MAD treatment.

Data and biological material

The patients participating in the study will all receive a questionnaire, the BerlinQ, and the ESS, which will be completed in the clinic using tablets and recorded in RedCap. The BerlinQ classifies patients into "low risk," "moderate risk," and "high risk" based on the extent of symptoms. The symptoms included in the BerlinQ are snoring (0-4 points), observed apnea (0-1 point), and daytime sleepiness (0-3 points). These are compared with overweight (BMI > 30 kg/m2) and/or hypertension. To fall under the "high risk" category, individuals must have at least two symptoms, i.e., > 4 points if they have no comorbidities, or > 2 points and a comorbidity. These "high-risk" patients will then be screened using Cardio-Respiratory Monitoring (CRM), which will monitor their sleep at home for one night. The severity of OSA will be defined based on the Apnea-Hypopnea Index (AHI). Patients diagnosed with OSA will then be referred for assessment for a mandibular advancement device (MAD) at the Maxillofacial Department K at OUH. See standard referral in the appendix. As part of the Same-Day Clinic (SDK), patients will undergo measurements of height, weight, automated blood pressure, HbA1c, lipids, s-creatinine, electrolytes, TSH, liver function tests, retinal photography for retinopathy determination, urinary albumin-to-creatinine ratio (U-ACR), foot examination with biothesiometry, and PRO questionnaire. Current medical treatment (including medications affecting pharyngeal tone), diabetes duration, alcohol and smoking status will be recorded. As part of the project, all individuals diagnosed with sleep apnea will undergo 24-hour ambulatory blood pressure monitoring 2-3 weeks before MAD placement and 3 months after the MAD appliance is adjusted. As part of the project, they will also be offered the BerlinQ, ESS, and CRM after 3 months of treatment (measured from the completion of appliance adjustment). For individuals with OSA, a dental and jaw status will be assessed prior to referral (number of teeth in each jaw, loose teeth, prostheses, jaw mobility (>6mm), and jaw pain). Neck circumference will be recorded. As part of the assessment on Department K for MAD, a Cone Beam CT scan will be performed, recording the minimal cross-sectional area of airways, as well as their location (retropharyngeal or retroglossal) and width. Additionally, the amount of mandibular advancement in the starting position and the size of the advancement arch when the patient is fully treated will be measured. Data will be manually entered into RedCap and pseudonymously stored for 5 years according to expected approval as a quality assurance project. All participants will have their height, weight, HbA1c, lipids, s-creatinine, electrolytes, TSH, liver function tests, U-ACR, and foot examination registered after 1 year as part of the SDK or alternatively, as part of the annual diabetes assessment

Collaborating researchers and departments

Department of Maxillofacial surgery

• Kasper Stokbro
• Christian Jakobsen