Mixed Message on Sleep Apnea Treatment Effect in Diabetes

Miriam E Tucker

April 05, 2016

Treatment of obstructive sleep apnea (OSA) with continuous positive airway pressure (CPAP) definitely benefits people who have the condition along with type 2 diabetes, but whether it improves blood glucose remains a matter of debate, as indicated by the conflicting results of two new studies.

Both studies were published online recently in the American Journal of Respiratory and Critical Care Medicine. One, by Elisabet Martínez-Cerón, MD, of Hospital Universitario La Paz, Madrid, Spain, and colleagues, found that among 50 patients with suboptimally controlled type 2 diabetes and OSA randomized to CPAP or placebo for 6 months, CPAP treatment improved glycemic control and insulin resistance.

"In these patients, a CPAP-induced reversion of the proinflammatory status seems to play an important role in A1c reduction," Dr Martínez-Cerón and colleagues write.

But the second study, by Jonathan E Shaw, MD, of the Baker IDI Heart and Diabetes Institute, Melbourne, Australia, and colleagues, showed no effect of CPAP on blood glucose in patients with relatively well-controlled type 2 diabetes, although the therapy did reduce diastolic blood pressure and daytime sleepiness and improved quality of life.

"The prevalence of OSA is high in type 2 diabetes, and clinicians should therefore have a high index of suspicion for it among patients with type 2 diabetes. We confirmed that using CPAP to treat sleep apnea in people with type 2 diabetes can be expected to lead to valuable clinical benefits, with reduced daytime sleepiness, better quality of life, and reduced blood pressure," Dr Shaw told Medscape Medical News.

However, he continued, "we found no evidence that it would improve glycemic control. Thus, while treatment of symptomatic OSA should still be pursued, we found no evidence to support screening for asymptomatic sleep apnea in type 2 diabetes, other than in the assessment of resistant hypertension."

CPAP Improves Glycemic Control…

In their open-label, parallel, and randomized clinical trial, Dr Martínez-Cerón and team randomized 50 adult patients with OSA and type 2 diabetes, HbA1c levels of 6.5% or greater on two occasions, and apnea-hypopnea index (AHI) of 5 or greater to CPAP or no active intervention for 6 months.

At baseline, they had a mean HbA1c of 7.6% and AHI of 32.1 events per hour. None had central sleep apnea. Just over half used oral glucose-lowering drugs alone, and about 42% used insulin (with or without oral agents).

They used CPAP an average of 5.2 hours per night, with 20 patients (77%) using it at least 4 hours per night. The mean pressure used was 8.1 cm H2O.

The adjusted 6-month CPAP effect on HbA1c levels was a drop from baseline of 0.4 percentage points (P = .029).

The per-protocol analysis of 18 CPAP patients and 24 controls produced similar adjusted results. Compared with the controls, the CPAP group showed a statistically significant 0.5-percentage-point decrease in HbA1c levels after 6 months (P = .017), whereas there were no significant differences between groups after 3 months.

And insulin sensitivity and insulin resistance both significantly improved with CPAP compared with the control arm (P = .013 and P = .023, respectively).

Similarly, patients treated with CPAP for 6 months also had lower levels of LDL cholesterol (P = .042) and of inflammatory cytokines IL-1β and IL-6 and higher levels of adiponectin. And they showed significant improvement on the satisfaction with treatment domain of the Diabetes Quality of Life (DQoL) questionnaire compared with controls (P = .043), but not on any other domains or total score.

In assessing the relationship between the absolute change in HbA1c after 6 months of CPAP therapy and the baseline characteristics of the subjects, only mean nocturnal oxygen saturation and IL-1β levels were retained as independent variables in a stepwise regression model (P = .002).

Interestingly, the authors note, a direct relationship was found between the change in IL-1β levels after 6 months and the change in HbA1c levels for both the study subjects overall (P = .001) and for patients treated with CPAP (P = .028).

…No, It Doesn't

The study by Dr Shaw and colleagues was an open-label, 6-month, randomized, parallel-group trial of CPAP therapy in patients with type 2 diabetes attending hospital and specialist clinics in Australia and North America.

Patients without a previous diagnosis of OSA were invited to be screened and were included if an overnight sleep study showed an oxygen desaturation index of 15 or more events per hour and they were aged 18 or older and had HbA1c values between 6.5% and 8.5%.

Participants were randomized 1:1 to usual care or usual care plus CPAP therapy. Data from 298 who met entry criteria were analyzed.

Mean CPAP therapy use was 4.3 hours per night at the 3-month visit and 4.9 hours at 6 months. Among 113 participants in the CPAP group with available data, mean residual AHI at 6 months was 6.2 events/hour. At 3 and 6 months, 45.8% and 61.3% of the patients were adherent to CPAP therapy, respectively.

In the usual-care group, body mass index (BMI) declined over the follow-up period.

No differences were seen between the two groups regarding change in HbA1c at 3 or 6 months (from baseline 7.3% in both groups to 7.2% for CPAP and 7.1% for usual care) or between the two groups after adjustment for differences in BMI.

Post hoc analyses showed there were no between-group differences in HbA1c change when the analysis was restricted to those with baseline HbA1c above 7.5% or those with moderate to severe sleep apnea (20 or more events per hour), nor were there differences between those in the CPAP group who were adherent to the therapy (ie, wore the device at least 4 hours/night) and those who weren't.

However, there was a greater fall in diastolic BP over 6 months in the CPAP-therapy group compared with the usual-care group (3.5 mm Hg vs 1.5 mm Hg, P = .07), again with a greater difference among those who were adherent to CPAP (–4.4 mm Hg vs –1.6 mm Hg, P = .02). No differences were observed for systolic blood pressure.

Daytime sleepiness, as measured by the Epworth Sleepiness Scale, also improved significantly more over 6 months with CPAP than with usual care (P < .0001), with no impact of adjustment for change in BMI.

Significant improvements were also seen in the CPAP-adherent patients on measures of vitality and mental health, remaining so after adjustment for BMI.

So Which Is Correct?

Asked to explain the differing findings, Dr Shaw pointed out that his group's study was considerably larger (298 vs 50) and was multicenter. He also noted that in the other study the CPAP group had more males (70% vs 30%), shorter diabetes duration (4.5 vs 7 years), and a higher mean AHI (35 vs 28) compared with the controls.

"The fact that these differences were not statistically significant is not important in considering whether they may have influenced the outcome," he told Medscape Medical News.

Moreover, 42% of the Spanish study's patients were on insulin, while that population was excluded in his group's study, he added.

Asked whether degree of adherence might explain the difference, Dr Shaw acknowledged that while usage of CPAP for 4 hours per night is a standard definition of adequate CPAP adherence, more recent data suggest that greater use may be needed in order to achieve metabolic benefits.

However, he said, "Although we still did not see reduction in HbA1c in those who were more adherent, the trial was not designed specifically to test this, and it is possible that we would have seen more benefits had adherence been greater."

"It is also worth noting that in asymptomatic individuals…achieving high levels of adherence to CPAP is very hard, and so even if there are beneficial effects on glycemic control at higher levels of adherence, it would be challenging to achieve this in clinical practice, especially as support for CPAP usage would generally be less in clinical practice than in a trial setting."

(Dr Martínez-Cerón's team did not respond to repeated requests for comment.)

Dr Martínez-Cerón's study was supported by grants from the Instituto de Salud Carlos III and from the Comunidad de Madrid. Dr Martínez-Cerón and coauthors report no relevant financial relationships. Dr Shaw's study was supported by ResMed Science Centre. Dr Shaw has received fees for serving on scientific advisory boards and has received speaker fees from Merck Sharp and Dohme, Novo Nordisk, Janssen, Takeda, AstraZeneca, Abbott, Sanofi, Novartis, and Pfizer. Disclosures for the coauthors are listed in the article.

Am J Respir Crit Care Med. Published online February 24, 2016, Abstract. Published online February 29, 2016, Abstract.

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