Obstructive sleep apnea (OSA) is a sleep disorder consisting of repetitive upper airway collapse that triggers hypoxemic episodes. OSA has been linked to increased risk of developing type 2 diabetes, as well as impaired glucose tolerance and elevated fasting glucose (1). Some studies have shown an association between OSA and nocturnal hyperglycemia in patients with type 2 diabetes (2).
Data on the effect of continuous positive airway pressure (CPAP) on glucose metabolism in patients with type 2 diabetes and OSA remain controversial, although some observational studies have revealed a significant reduction in mean nocturnal glucose levels with CPAP administration in patients with type 2 diabetes and severe OSA (3).
Herein, we present the case of a patient with type 2 diabetes presenting with refractory fasting hyperglycemia in the setting of OSA who was identified through continuous glucose monitoring (CGM) to have nocturnal hyperglycemia, which significantly improved after 5 weeks of CPAP therapy.
Case Presentation
A 59-year-old male patient with a history of type 2 diabetes, severe obesity (BMI 36.19 kg/m2), and hyperlipidemia presented for a routine follow-up visit for management of his type 2 diabetes, with an A1C of 9.9%. The patient was diagnosed with type 2 diabetes at the age of 49 years with an A1C of 13%. He was initially started on oral agents, with insulin added to his medication regimen 3 years later.
He had persistent fasting hyperglycemia despite high doses of basal and bolus insulin: insulin glargine 130 units and insulin aspart 1 unit per 5 g carbohydrates before each meal, plus sliding scale insulin for correctional doses. He was also taking empagliflozin 25 mg daily, dulaglutide 0.75–1.5 mg once weekly, and the insulin sensitizers pioglitazone 45 mg daily and regular metformin 1,000 mg daily. The changes in his medications and insulin requirements are shown in Table 1.
Evolution of the Diabetes Medication Regimen Before and After CPAP Therapy
| Time Since Initial Visit, months | Insulin Glargine, units/day | Insulin Aspart, insulin unit:g carbohydrate (total units/day) | Empagliflozin, mg/day | Regular Metformin, mg/day | Pioglitazone, mg/day | Dulaglutide, mg/week | |
|---|---|---|---|---|---|---|---|
| Pre-CPAP | 0 | 130 | 1:5 (145) | 25 | 1,000 | 45 | 0.75 |
| 7 | 140 | 1:5 (145) | 25 | 1,000 | 45 | 1.5 | |
| 13.5 | 150 | 1:5 (140) | 25 | 1,000 | 45 | 1.5 | |
| 23.5 | 150 (NPH 30 units added) | 1:5 (155) | 25 | 1,000 | Discontinued | 1.5 | |
| 27.5 | 140 (NPH increased to 40 units) | 1:5 (148) | 25 | 1,000 | — | 1.5 | |
| Post-CPAP | 29 | 50 (No NPH) | 1:5 (96) | 25 | 1,000 | — | 1.5 |
| Time Since Initial Visit, months | Insulin Glargine, units/day | Insulin Aspart, insulin unit:g carbohydrate (total units/day) | Empagliflozin, mg/day | Regular Metformin, mg/day | Pioglitazone, mg/day | Dulaglutide, mg/week | |
|---|---|---|---|---|---|---|---|
| Pre-CPAP | 0 | 130 | 1:5 (145) | 25 | 1,000 | 45 | 0.75 |
| 7 | 140 | 1:5 (145) | 25 | 1,000 | 45 | 1.5 | |
| 13.5 | 150 | 1:5 (140) | 25 | 1,000 | 45 | 1.5 | |
| 23.5 | 150 (NPH 30 units added) | 1:5 (155) | 25 | 1,000 | Discontinued | 1.5 | |
| 27.5 | 140 (NPH increased to 40 units) | 1:5 (148) | 25 | 1,000 | — | 1.5 | |
| Post-CPAP | 29 | 50 (No NPH) | 1:5 (96) | 25 | 1,000 | — | 1.5 |
By 2 years after the initial visit, the patient required increasingly more insulin, with nighttime glargine at 150 units. He mentioned significant snoring and severe daytime sleepiness. A sleep study was ordered, and 30 units nighttime NPH insulin was added to his regimen after CGM confirmed the presence of nocturnal hyperglycemia. He was diagnosed with OSA with an apnea hypopnea index of 23.1 events/hour and started on CPAP shortly thereafter.
CGM data recorded 5 weeks after the start of CPAP therapy, as shown in Table 2, revealed significantly improved nocturnal hyperglycemia, and the patient’s A1C 25 weeks after starting CPAP therapy was 7.4%, down from 9.9% 14 weeks before the start of CPAP therapy. His nighttime glargine dose decreased to 50 units, and NPH was discontinued because of nocturnal and fasting hypoglycemic episodes. Figure 1 displays the CGM tracings before (upper panel) and after (lower panel) CPAP therapy.
CGM Data Before and After CPAP
| Before CPAP | After CPAP | |
|---|---|---|
| Duration, days | 15 | 14 |
| Time CGM is active, % | 100 | 100 |
| Average glucose, mg/dL | 195 | 127 |
| Glucose management indicator, % | 8.0 | 6.3 |
| Coefficient of variation, % | 30 | 38 |
| Times in ranges, % Time above range, very high (>250 mg/dL) Time above range, high (181–250 mg/dL) Time in range (70–180 mg/dL) Time below range, low (54–69 mg/dL) Time below range, very low (<54 mg/dL) | 15 45 39 0 1 | 1 16 71 9 3 |
| Before CPAP | After CPAP | |
|---|---|---|
| Duration, days | 15 | 14 |
| Time CGM is active, % | 100 | 100 |
| Average glucose, mg/dL | 195 | 127 |
| Glucose management indicator, % | 8.0 | 6.3 |
| Coefficient of variation, % | 30 | 38 |
| Times in ranges, % Time above range, very high (>250 mg/dL) Time above range, high (181–250 mg/dL) Time in range (70–180 mg/dL) Time below range, low (54–69 mg/dL) Time below range, very low (<54 mg/dL) | 15 45 39 0 1 | 1 16 71 9 3 |
Questions
Does untreated OSA cause nocturnal hyperglycemia in patients with type 2 diabetes?
If so, why and how does OSA cause nocturnal hyperglycemia?
Does appropriate treatment of OSA with CPAP ameliorate nocturnal hyperglycemia?
Commentary
The prevalence of OSA varies widely among different age-groups but is more common in individuals with obesity. In addition to the commonly reported sleepiness, tiredness, and snoring, underestimated symptoms of OSA may include morning headaches, nocturia, acid reflux, and dysphagia (4). With regard to OSA’s link to type 2 diabetes, an early observational study showed a strong inverse relationship between severity of OSA and glycemic control (5). Since then, stronger evidence has linked OSA to an increased risk of developing diabetes, as well as impaired glucose tolerance, glucose dysregulation, and elevated fasting glucose (1).
A few studies have shown an association between OSA and nocturnal hyperglycemia, as observed in this case (2). A cross-sectional study found that the nocturnal interstitial glucose level was significantly higher in severe and moderately hypoxemic groups during sleep studies. The study revealed peaks of nocturnal hyperglycemia after hypoxemic episodes (2). Another observational study using polysomnography and CGM data simultaneously found that patients with OSA and diabetes had a mean nocturnal glucose level 38% higher than those without OSA (2).
Although the pathophysiological mechanisms explaining the link between OSA and nocturnal hyperglycemia remain unclear, stimulation of the stress response, including activation of the sympathetic nervous system and release of cortisol, is thought to play a major role. A study in adolescents with obesity found that those with OSA had significantly higher salivary cortisol levels measured at 1:00, 7:00, and 11:00 p.m., potentially indicating a chronically strained hypothalamus-pituitary-adrenal axis (6). As most of these findings have been purely observational, there is a need for mechanistic studies to investigate the association between OSA and hyperglycemia.
The presented case is an example of nocturnal hyperglycemia in a patient with undiagnosed OSA that improved substantially after 5 weeks of consistent CPAP use. Nevertheless, the effect of CPAP on glucose homeostasis in patients with type 2 diabetes remains unclear. One systemic review and meta-analysis that included six studies (one randomized controlled trial [RCT] and five observational studies) concluded that 12 weeks of CPAP use does not decrease A1C but does have a beneficial effect on insulin sensitivity (7). Similarly, a clinical trial found no effect of 12 weeks of CPAP therapy on CGM-measured mean glucose levels, time with hyperglycemia, or glucose variability in patients with OSA and type 2 diabetes. However, only 44% of the intervention group was compliant with the CPAP therapy (8).
Similarly, an RCT investigated the effects of 12 weeks of CPAP therapy on glucose tolerance in patients without diabetes but with morbid obesity and severe OSA. It found that CPAP was associated with improved glucose tolerance without a change in insulin resistance (9).
In conclusion, the effect of CPAP in patients with OSA and diabetes remains uncertain. There is a need for more studies to assess the impact of the OSA phenotype on glucose metabolism and insulin resistance to further elucidate the underlying mechanisms (10). This case report highlights the effect of CPAP on nocturnal hyperglycemia in a patient with type 2 diabetes, insulin resistance, and severe OSA.
Clinical Pearls
OSA can cause nocturnal hyperglycemia, which is important to consider in patients presenting with elevated fasting glucose.
OSA-induced nocturnal hyperglycemia is thought to be a consequence of increased levels of stress hormones.
CPAP can have a significant effect in ameliorating nocturnal hyperglycemia and insulin resistance; however, this effect has not been consistent in clinical studies.
Article Information
Duality of Interest
No potential conflicts of interest relevant to this article were reported.
Authorship Contributions
A.D. collected data, wrote the initial draft, and contributed to the final manuscript. S.H. interpreted the sleep studies and contributed to the final manuscript. J.L. collected data and contributed to the initial draft and final manuscript. J.L. is the guarantor of this work and, as such, had full access to all the data in this report and takes responsibility for the integrity and accuracy of the information reported.
