**6. Interactions of chronic obstructive pulmonary disease, sleep apnea hypopnea syndrome and diabetes** *mellitus* **treatment modalities**

The treatment that has shown to increase survival in COPD is smoking cessation. This is the only measure that slows the accelerated decline in lung function in these patients. COPD therapeutic approach is based on: inhaled bronchodilators, inhaled and systemic corticosteroids, pulmonary and muscular rehabilitation, anti-inflammatory drugs, oxygen and palliative symptomatic treatment in the latter stages of the disease. In a greater or lesser extent, these treatments can influence the glycemic control of DM.

To begin with, systemic corticosteroids clearly alter the metabolism of carbohydrates. Corticosteroid treatment increases upperway resistance due to fluid retention in addition to myopathy and metabolic alkalosis. In addition, corticosteroids may predispose to SAHS by promoting central obesity. Among the most widely used, methylprednisolona is the one that worsens glycemic control the most, followed by hydrocortisone. Deflazacort has less effect on diabetic control.

We can not ignore the possible effect of inhaled corticosteroids on glycemic control. Many DM patients follow an inhaled drugs schedule for their coexistent COPD. Although considered a safe treatment, some systemic effects have been described. Cataracts and suppression of the hypothalamic-pituitary-adrenal are possible effects when maximum dose are given (Faul et al., 2009). In addition, some studies have shown (Faul et al., 1998) a significant increase (1.0%) in glycated hemoglobin and the persistence of glycosuria in

CRP interaction with Fcgamma receptor (Fcγ R) possibly increases the monocyte chemokine MCP-1 production, leading to monocyte adherence on to the arterial wall (Sevenoaks & Stockley, 2006). CRP also facilitates the production of foam cells that give shape to the atherosclerotic plaque. The "Third National Health and Nutrition Examination Survey" (NHANES III) denoted an association between CRP and myocardial ischemia. CRP levels higher than 3 mg/dl are significantly related to future cardiovascular events (Pai et al., 2004). This level is commonly surpassed in COPD patients. NF-κβ and TNF-α pathways leading to cardiovascular disease deserve a thorough research in COPD, SAHS and overlap syndrome. TNF- α induces the expression of CRP in the liver, being at the core of the process. TNF- α also has an active effect on macrophages migration, adhesion and differentiation within the atheroma plaque (Sevenoaks & Stockley, 2006). During COPD acute exacerbations, a further rise in CRP levels is also followed by a rise in fibrinogen as the expression of a thrombosis risk. Of note, cardiovascular mortality is particularly enhanced within and following hospital admission for an acute exacerbation (Sevenoaks & Stockley,

Briefly, the common consequence of COPD, SAHS, MS and DM is an inflammatory status that culminates in endothelial dysfunction leading to cardiovascular events. A novel explanation for the convergent endothelial dysfunction is a depletion or low response of bone marrow stem-cells. This phenomenon determines a reduction of circulating endothelial progenitor cells (EPC). Hyperglycemia, obesity, hypertension and dyslipidemia have been associated with a reduction of circulating EPC. Moreover, a synergistic reduction of EPC has been associated to the clustering of metabolic disruptions (Fadini et al., 2007; Werner et al.,

**6. Interactions of chronic obstructive pulmonary disease, sleep apnea hypopnea syndrome and diabetes** *mellitus* **treatment modalities** 

extent, these treatments can influence the glycemic control of DM.

The treatment that has shown to increase survival in COPD is smoking cessation. This is the only measure that slows the accelerated decline in lung function in these patients. COPD therapeutic approach is based on: inhaled bronchodilators, inhaled and systemic corticosteroids, pulmonary and muscular rehabilitation, anti-inflammatory drugs, oxygen and palliative symptomatic treatment in the latter stages of the disease. In a greater or lesser

To begin with, systemic corticosteroids clearly alter the metabolism of carbohydrates. Corticosteroid treatment increases upperway resistance due to fluid retention in addition to myopathy and metabolic alkalosis. In addition, corticosteroids may predispose to SAHS by promoting central obesity. Among the most widely used, methylprednisolona is the one that worsens glycemic control the most, followed by hydrocortisone. Deflazacort has less effect

We can not ignore the possible effect of inhaled corticosteroids on glycemic control. Many DM patients follow an inhaled drugs schedule for their coexistent COPD. Although considered a safe treatment, some systemic effects have been described. Cataracts and suppression of the hypothalamic-pituitary-adrenal are possible effects when maximum dose are given (Faul et al., 2009). In addition, some studies have shown (Faul et al., 1998) a significant increase (1.0%) in glycated hemoglobin and the persistence of glycosuria in

2006; Smeeth et al., 2004).

on diabetic control.

2005, as cited in Tiengo et al., 2008).

patients with DM 2 who used high-dose inhaled fluticasone (2 mg / day). Other study (Slatore et al., 2009), shows that high dose of inhaled corticosteroids are associated with small changes in glycemic control that are detectable but not clinically relevant as they would not be a criteria to stop or change the treatment.

One shared mainstay of COPD and DM treatment is physical exercise. Physical activity improves lung function and provides a better tolerance of the obstructive disease. It also reduces the risk of type 2 DM (13) and improves glycemic control with a lower dose of antidiabetic agents.

Weight loss can clearly be of benefit for patients with SAHS, obesity and/or DM. Probably, a benefit can be obtained in not advanced COPD stages with excessive weight. Weight loss improves SAHS but does not cure it. In a meta-analysis about bariatric surgery and SAHS, the baseline AHI was reduced from 54.7 to 15.8 events per hour, the latter indicating a moderate to severe SAHS still remaining (Greenburg et al., 2009). Patients should be alerted that they will probably need to continue SAHS treatment after surgery. Clinicians should also be aware that weight loss is associated with increased mortality in COPD. There is no evidence to recommend weight loss in overlap syndrome.

In an indirect way, the oxygen prescribed in advanced lung disease may also influence the management of diabetes. Unfortunately we lack solid studies to verify it. The hypothesis is that control of hypoxia may improve glucose tolerance and the associated MS. CPAP treatment of SAHS has not shown to improve metabolic syndrome in obese patients (Vgontzas et al., 2008), whereas it reduces visceral fat in non obese patients (Chin et al., 1999).

As we have described how hyperglycemia may worsen COPD outcome, we could pose if diabetes treatment can improve respiratory function. Being type 2 the most prevalent DM among COPD patients, insulin sensitizers could improve the lung function. This hypothesis was tested by Kim and colleagues (Kim et al., 2010) in a retrospective cohort study. After adjustment by weight, height and glycemic control, they found an improvement of FVC in subjects treated with insulin sensitizers compared to other DM treatments, with no significant changes in FEV1 or in FEV1/FVC.

We wonder if the new anti-inflammatory drugs (anti-phosphodiesterase 4) may have an effect on control of DM trying to improve the chronic inflammation of COPD. Modulators of the oxidative process such as methyl-bardoxolona are a possibility to be explored in both chronic conditions.
