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The Impact of Treatment of Obstructive Sleep Apnoea Syndrome on Glycaemic Control in Patients with Diabetes Mellitus

Published Online: June 6th 2011 European Endocrinology, 2007(1):62-4; DOI: http://doi.org/10.17925/EE.2007.00.01.62
Authors: Anne-Katrin Schober, Eckhart G Hahn, Igor A Harsch
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Abstract:
Overview

Obesity is, typically, a common feature of both type 2 diabetes mellitus and of obstructive sleep apnoea syndrome (OSAS). Thus, it seems reasonable to be suspicious of some overlap between the two disease entities. For example, in a French study, 595 males with suspected OSAS underwent both nocturnal polysomnography and a two-hour ora glucose-tolerance test. OSAS was confirmed in 494 patients; type 2 diabetes was present in 30.1% and impaired glucose tolerance (IGT) was diagnosed in 20.0% of the patients.1

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These findings suggest a significant overlap between the two diseases, but this clinic-based sample of obese patients (body mass index (BMI) 30.6±0.2) had been selected on the basis of presentation with typical symptoms of OSAS.

These findings suggest a significant overlap between the two diseases, but this clinic-based sample of obese patients (body mass index (BMI) 30.6±0.2) had been selected on the basis of presentation with typical symptoms of OSAS. However, a Japanese study of OSAS patients also showed a high prevalence of diabetes or IGT in 34 patients, 13 were diagnosed with diabetes mellitus (38.2%); 12 with a pathological glucose tolerance (35.3%); and only nine subjects had a normal response (26.5%) in an oral glucose-tolerance test.2 These studies investigated subjects with confirmed OSAS for disturbances in glucose metabolism. It is not currently known how many patients with confirmed diabetes mellitus also suffer from OSAS, especially when they do not present with the typical symptoms of OSAS

Obstructive Sleep Apnoea Syndrome and Insulin Resistance
A typical metabolic feature of both type 2 diabetes and OSAS is insulin resistance. The presence of increased insulin resistance has repeatedly been reported in patients with OSAS. In recent years, several investigators reported insulin resistance to be an independent feature of the OSAS apart from the role of the typical obesity of these patients.3–5Some authors have speculated that, in patients with OSAS, the increased nsulin resistance is at least partially mediated by increased sympathetic activity caused by frequent nocturnal micro-arousals and nocturna hypoxaemia.6–8 Since micro-arousals and hypoxaemia can be effectively overcome by adequate nasal continuous positive airway pressure (CPAP) therapy, a reduction of insulin resistance in OSAS patients could be expected. Given that these patients also suffer from type 2 diabetes with nsulin resistance – a key feature of this condition – one could easily speculate about an improvement of glycaemic control by CPAP therapy in patients with both conditions. However, recent studies provide evidencethat the insulin resistance is an independent feature of OSAS and can be mproved with CPAP therapy;5 these studies have also demonstrated that obesity was the main determinant of insulin resistance in these patients. It is still unclear whether CPAP treatment can reduce the insulin resistance to a degree necessary to improve glycaemic control in diabetic patients.

Influence of Continuous Positive Airway Pressure Therapy on Diabetes Mellitus
To date, there have been only a few published reports on the effect of CPAP therapy in patients suffering from both type 2 diabetes mellitus and OSAS.912 The parameters of these studies are presented in Table 1The first study presented on the topic demonstrated a significant increase in insulin sensitivity in a group of nine very obese patients with type 2 diabetes and OSAS after three months of CPAP treatment.9 A strong point of the study was the use of euglycaemic hyperinsulinaemic clamp tests to determine insulin sensitivity. The study had some limitations.The patients in the study population had considerable obesity and had different antidiabetic treatment modes (insulin, oral antidiabetic drugs or diet alone) without sufficient glycaemic control. There is also a lack of information regarding changes in lifestyle during the treatment period (e.g. exercise, alcohol and nicotine consumption), concomitant diseases such as hypertension, the duration of diabetes and the absence or presence of autonomous diabetic neuropathy, which is itself a known risk factor for OSAS.13 Unfortunately, the reported improvement of insulin sensitivity was not accompanied by an improvement in haemoglobin A1c (HbA1c) levelsAgainst this background, the authors’ study group investigated nine subjects with well-controlled diabetes mellitus before, two days after and three months after onset of CPAP therapy with the euglycaemic hyperinsulinaemic clamp procedure.10 The study failed to demonstrate rapid significant changes of insulin sensitivity after two nights of CPAP treatment, but, after three months of effective CPAP treatment, insulin sensitivity was significantly improved. However, there was also no mprovement in the HbA1c or fructosamine levelsA 2005 control study measured interstitial glucose continuously over a period of 72 hours before and after CPAP treatment in 25 patients with type 2 diabetes and OSAS.11 The mean one-hour postprandial (breakfast, dinner, lunch) glucose levels were significantly lower after a CPAP treatment period of 83+50 days. HbA1c levels were also improved by CPAP treatmentIn this study, the adequate and regular use of CPAP therapy was very mportant. In patients using their CPAP device regularly and for more than four hours per night, the decrease in HbA1c levels and blood-glucose values was more distinct than in the subgroup with less CPAP therapy adherence. Furthermore, the improvement in glycaemic control was greater in the more poorly controlled patients (i.e. higher baseline HbA1c value).

Table 1: Data from Studies Investigating the Effect of Continuous Positive Airway Pressure Therapy on Glycaemic Control in Diabetic Patients (Without Relevant Changes in Antidiabetic Therapy)

Author

Brooks9

Harsch10

Babu11

Hasaballah12

Number of patientsa

9

9

24

38

Diabetes therapy (combined with diet)

OAD Insulin

OAD

OAD nsulin Insulin + OAD

OAD nsulin

BMI (kg/m2)

42.2±4.3

37.3±5.6

42.7±8.7

42±9.5

Study duration

Four months

91.4±35.5

days

83±50 days

134±119 days

Degree of OSAS

Severe

Severe

Severe

Severe

Insulin sensitivity (Clamp)

Signs of improvement

Signs of improvement

No difference

No difference

HbA1c at onset of study

8.9±1.5%

6.4±0.7%

8.3±2.2%

7.8±1.4%

HbA1c at end of study

8.9±1.2%

6.3±0.6%

7.9±2.0%b 8.7±2.5%c

7.3±1.3%

a. Number of patients who completed the study; b. CPAP therapy per night >4 hours; c. CPAP therapy per night <4 hours. OAD: oral antidiabetic drugsA significant improvement in HbA1c in severely obese patients with type 2 diabetes and severe OSAS due to CPAP therapy has also been demonstrated.12To summarise, although there seems to be a tendency towards an mprovement of glucose metabolism in diabetic patients the worse their glycaemic control and given not too many co-morbidities, these studies suffer from low patient numbers and sometimes very heterogeneous samples and cover a short time span

Clinical End-points
Apart from judging the effectiveness of the treatment by surrogate parameters such as HbA1c, several colleagues know from experience that it is easier to achieve stable blood glucose profiles in diabetic patients with OSAS who are effectively treated by CPAP – an observation that stil requires further confirmation in studiesFrom the diabetologist’s point of view, there is still a requirement for research to address the effect of CPAP on glucose metabolism. There is a lack of long-term studies, since the studies addressing glucose metabolism, previously described in detail, cover only a few monthsThe fate of patients with diabetes mellitus and OSAS is typically determined by cardiovascular complications.13 Long-term studies on these ‘hard’ end-points in patients with both diseases are currently not available. However, clinically beneficial effects of CPAP therapy in severa studies with OSAS patients – sometimes also including a few diabetic subjects – have been demonstrated, and give cause for optimism that these results may also be applicable to patients with both diseases. In OSAS patients, there is evidence that adequate CPAP therapy reduces the mean arterial blood pressure, improves the left ventricular ejection fraction and significantly decreases the risk of fatal and non-fata cardiovascular events (in 372 patients with treated OSAS versus 235 untreated patients with severe OSAS and 403 untreated patients with mild or moderate OSAS).1416 Furthermore, CPAP therapy raises high-density lipoprotein cholesterol after six months of therapy.17

Open Questions
Another fascinating question, as yet unanswered, is whether CPAP therapy in prediabetic patients with OSAS (e.g. patients with impaired fasting glucose or pathological glucose-tolerance testing) have a risk reduction to developing overt type 2 diabetes mellitus due to CPAP therapy. A possible mechanism favouring such a hypothesis could be the mprovement in insulin sensitivity observed in many studies due to CPAP therapy. Whether this degree of reduction of insulin resistance is sufficient to have preventive effects is as yet unknownThe observations and studies mentioned in this article refer to patients with OSAS alone or with OSAS and type 2 diabetes. Although not driven by insulin resistance – but sometimes also causing sleep disturbances or sleep-disordered breathing by neuropathic complications – the possible mplications of treatment of sleep-disordered breathing in type 1 diabetic patients is largely unknown.18

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References

  1. Meslier N, Gagnadoux F, Giraud P, et al., Impaired glucoseinsulin metabolism in males with obstructive sleep apnoea syndrome, Eur Respir J, 2003;2:156–60.
  2. Katsumata K, Okada T, Miyao M, Katsumata Y, High incidence of sleep apnea syndrome in a male diabetic population, Diabetes Res Clin Pract, 1991;13(1-2):45–51.
  3. Ip MS, Lam B, Ng MMT, et al., Obstructive sleep apnea is independently associated with insulin resistance, Am J Respir Crit Care Med, 2002;165:670–76.
  4. Punjabi NM, Sorkin JD, Karzel LI, et al., Sleep-disordered breathing and insulin resistance in middle-aged and overweight men, Am J Respir Crit Care Med, 2002;165:677–82.
  5. Harsch IA, Pour Schahin S, Radespiel-Tröger M, et al., Continuous positive airway pressure treatment rapidly improves insulin sensitivity in patients with obstructive sleep apnea syndrome, Am J Respir Crit Care Med, 2004;169:156–62.
  6. Coy TV, Dimsdale JE, Ancoli IS, Clausen J, Sleep apnoea and sympathetic nervous system activity: a review, J Sleep Res, 1996;5:42–50.
  7. Marrone O, Riccobono L, Salvaggio A, et al., Catecholamines and blood pressure in obstructive sleep apnea syndrome, Chest, 1993;103:722–7.
  8. Hedner JA, Darpo B, Ejnell H, et al., Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications, Eur Respir J, 1995;8:222–9.
  9. Brooks B, Cistulli PA, Borkman M, et al., Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effect of continuous positive airway pressure treatment on insulin responsiveness, J Clin Endocrinol Metab, 1994;79:1681–5.
  10. Harsch IA, Schahin SP, Brückner K, et al., The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes, Respiration, 2004;71:252–9.
  11. Babu AR, Herdegen J, Fogelfeld L, et al., Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea, Arch Intern Med, 2005;165:447–52.
  12. Hassaballa HA, Tulaimat A, Herdegen JJ, Mokhlesi B, The effect of continuous positive airway pressure on glucose control in diabetic patients with severe obstructive sleep apnea, Sleep Breath, 2005;9:176–80.
  13. Stoohs RA, Guilleminault C, Malone S, et al., Cardiovascular changes associated with obstructive sleep apnea syndrome, Chest, 1991;22:1021–5.
  14. Pepperell JCT, Ramdassingh-Dow S, Crosthwaite N, et al., Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea. A randomized parallel trial, Lancet, 2001;359:204–10.
  15. Yaneko Y, Floras JS, Usui K, et al., Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructice sleep apnea, N Engl J Med, 2003;348:1233–41.
  16. Marin JM, Carrizo SJ, Vicente E, Agusti AG, Long-term cardiovascular outcomes in men with obstructive sleep apnoea, hypopnoea with or without treatment with continuous positive airway pressure: an observational study, Lancet, 2005;365:1046–53.
  17. Borgels J, Sanner BM, Bitlinski A, et al., Obstructive sleep apnoea and its therapy influence high-density lipoprotein cholesterol serum levels, Eur Respir J, 2006:27:121–7.
  18. Ficker JH, Dertinger SH, Siegfried W, et al., Obstructive sleep apnoea and diabetes mellitus: the role of cardiovascular autonomic neuropathy, Eur Respir J, 1998;11(1):14–19.

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