Reviewing the effects of hyperglycemia and diabetes mellitus on COPD

Diabetes mellitus is a group of disorders characterized by hyperglycemia and the resulting macrovascular and microvascular complications. The prevalence of diabetes is on the rise in the United States; in 2007, 23.6 million persons had diabetes, 17.9 million received the diagnosis, and another 5.7 million persons had diabetes that remained undiagnosed.¹

The US health care costs of diabetes are staggering and continue to grow. Based on prevalence and demographic data from 2007, the total estimated cost of diabetes is $174 billion: $116 billion in excess medical expenditures and $58 billion as a result of a reduction in national productivity. In addition, 50% of the medical expenditure cost is attributable to hospital inpatient care related to diabetes.²

Diabetes is a leading cause of morbidity and death as a result of its systemic manifestations, and its effects on the renal, cardiovascular, and nervous systems have been well described.³ Several population-based epidemiological studies have documented reduced ventilatory function among patients with diabetes; in fact, the prevalence of coexisting chronic obstructive pulmonary disease (COPD) and diabetes is 1.6% to 16%.^4,5

In this article, we review the current knowledge regarding the relationship between diabetes mellitus and chronic lung disease.

DIABETES AND LUNG FUNCTION

Diabetes mellitus has been associated with abnormalities in markers of systemic inflammation and with an increased risk of other diseases, such as cardiovascular disease. Several studies suggest that diabetes is associated with impaired pulmonary function.^6-8

Walter and associates⁸ explored the relationship of diabetes and of fasting blood glucose concentration to the level of pulmonary function, using data from the Offspring Cohort of the Framingham Heart Study. They found that a diagnosis of diabetes was associated with a lower mean adjusted forced expiratory volume in 1 second (FEV₁) and forced vital capacity (FVC). This relationship was more pronounced in current smokers than in those who had never smoked. Regardless of smoking status, the mean residual FEV₁ decreased with increasing fasting blood glucose level. The patients in the highest quartile of fasting blood glucose had an average residual FEV₁ that was 85 mL lower than those in the lowest quartile.

The prevalence of diabetes and acute hyperglycemia has been shown to be increased in patients with COPD.⁹ In a prospective cohort study, Rana and associates¹⁰ found that women with COPD had a 1.8-fold increased risk of type 2 diabetes mellitus. However, this association was not found in women who had asthma. Overall, 14% to 15% of patients with COPD admitted to the hospital have diabetes.¹¹

The temporal relationship between diabetes and reduced lung function and the clinical significance of the association between the two are not clearly understood. Possible links between respiratory impairment and diabetes may be attributable to increased body mass index, subsequent loss of respiratory compliance, neuropathies, loss of strength of the respiratory muscles, and other confounding variables.¹² Multiple studies suggest that the lung is an end-organ target for damage induced by sustained hyperglycemia. Histological evidence obtained from the lungs of diabetic patients reveals changes in the microvasculature, such as thickening of the pulmonary capillary basal laminae.¹³ However, the association between these histological changes and the occurrence of clinical disease remains unclear. Other studies indicate that reduced ventilatory function, as measured by FVC, FEV₁, and carbon monoxide–diffusing capacity, may be a risk factor for impaired glucose tolerance and overt diabetes mellitus.^6,12,14

The pathogenesis of COPD is thought to involve the up-regulation of inflammatory cells and markers with subsequent connective-tissue degradation, an inflammatory event that is usually spurred by smoking.¹⁵ In fact, the annual decline in FEV₁ is steeper in smokers than in nonsmokers. Systemic inflammatory markers, such as interleukin (IL)-1, IL-6, and tumor necrosis factor-α (TNF-α), have been shown to play a role in the development of COPD and are associated with increased insulin resistance, and several studies have elucidated the association between higher levels of inflammatory markers and type 2 diabetes mellitus.^16-22

Thus, lung function and insulin resistance may be independently influenced by systemic inflammation.²³ Advanced glycosylation end-products can alter matrix proteins and influence endothelial cell expression of cytokines and other inflammatory markers.²⁴ If diabetes is proinflammatory, then impairment of glycemic control may cause ventilatory dysfunction, either independently or synergistically with smoking exposure.⁸

Litonjua and colleagues²⁵ conducted a nested case-control analysis using the cohort from the Normative Aging Study to explore the relationship between type 2 diabetes mellitus and lung function. The Normative Aging Study was instituted in 1961 by the Veterans Administration to investigate the process of aging; healthy persons were chosen from the Boston area, and those with chronic medical ailments were excluded.²⁶ Participants in the study had diminished lung function several years (median, 13.6 years) before the diagnosis of diabetes. The authors concluded that glycosylation of proteins in the lung prompted by hyperglycemia may lead to damage to the lung tissue, which eventually progresses to clinically evident disease.^25,27

The Fremantle Diabetes Study also explored the relationship between pulmonary function and type 2 diabetes mellitus.⁷ The study was conducted in Australia with persons of Anglo-Celt/European descent and no history of chronic lung disease. The results were in concordance with those of previous studies: predicted values of FVC, FEV₁, vital capacity, and peak expiratory flow were, on average, at least 9.5% lower in diabetic than in nondiabetic persons.^15,26 Regression analysis indicated that the duration of diabetes was an independent predictor of reduced pulmonary function. There was no association between glycemic control and spirometric measures. This suggests a more complicated pathophysiology of diabetes-related lung disease than previously proposed.

In contrast, pulmonary function was not associated with known or newly diagnosed type 2 diabetes mellitus in a group of older persons in the Rancho Bernardo Study.²⁸ However, the duration of diabetes (10 or more years) was associated with reduction in age- and height-adjusted FEV₁ in men. Since this gender-specific correlation was revealed in post hoc analysis, it warrants further analysis. There are several possible explanations for why lung function was not associated with diabetes in the Rancho Bernardo Study: the population was older (72.3 years) and men and women who had both diabetes and pulmonary disease may have been lost because of death or morbidity, leading to a selection bias.

Metabolic syndrome and COPD

Metabolic syndrome is a complex constellation of risk factors for cardiovascular disease as well as for diabetes. In 1988, Reaven²⁹ first described metabolic syndrome, also known as syndrome X, as a factor in diabetes mellitus, hypertension, and atherosclerotic heart disease with dyslipidemia.

The risk factors that characterize the metabolic syndrome include abdominal obesity; atherogenic dyslipidemia; hypertension; insulin resistance; and defects in inflammation, coagulation, and fibrinolysis. The diagnostic criteria based on the consensus statement by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) are as follows: waist circumference greater than 102 cm in men and 88 cm in women, fasting triglyceride levels of 150 mg/dL or higher, high-density lipoprotein cholesterol levels of less than 40 mg/dL in men and less than 50 mg/dL in women, blood pressure of 130/85 mm Hg or higher, and fasting blood glucose levels of 110 mg/dL or higher.³⁰

A number of reports have established that patients with COPD are at greater risk for cardiovascular disease–related death, but the nature of this association remains largely undefined.^31-33 In 2005, Marquis and colleagues³⁴ hypothesized that an increased prevalence of metabolic syndrome in patients with COPD may explain this association. They evaluated the prevalence of metabolic syndrome in COPD patients who participated in a cardiopulmonary rehabilitation program in Canada. The prevalence of metabolic syndrome was higher in participants with COPD (n = 38, 47%) than in a control group without COPD and cardiovascular disease in the general population (n = 34, 21%) matched for age and sex.³⁴ The NCEP ATP III criteria were used for evaluating patients for metabolic syndrome. The criteria included indentifying 3 or more of the following features: abdominal obesity (waist circumference of more than 102 cm in men and more than 88 cm in women), triglyceride levels of 1.69 mmol/L or higher, high-density lipoprotein cholesterol levels of less than 1.0 mmol/L in men and less than1.3 mmol/L in women, blood pressure of 130/85 mm Hg or higher, and fasting glucose levels of 6.1 mmol/L or higher.

This relationship was not established for women with COPD. The prevalence of metabolic syndrome was higher in women with COPD than in the control group, but was lower than in age-matched women without COPD in the general population. The investigators proposed that the chronic debilitation and sedentary lifestyle resulting from COPD could explain the relationship between COPD and metabolic syndrome. However, further study is warranted to fully delineate this association. Generalization from the above-mentioned study is limited because the study included only Caucasians, and the prevalence of metabolic syndrome varies among ethnic groups. Thus, these findings cannot be confidently generalized to the multiethnic population of the United States.

Lawlor and associates³⁵ proposed a more dynamic approach to the relationship between lung function and type 2 diabetes mellitus. They performed a cross-sectional study of almost 4000 elderly women from the British Women’s Heart and Health Study. FVC and FEV₁ were measured, and blood samples were taken to measure levels of fasting glucose, insulin, and proinsulin. Insulin resistance was calculated using the homeostasis model assessment (the product of fasting glucose and insulin divided by a constant). This measure was used only in nondiabetic persons, because it has been proved to be less accurate in elderly diabetic patients. Leg length was used as a biomarker for early life environmental exposures affecting growth.

The major findings of this study were that the measures of lung function were inversely correlated with the presence of insulin resistance and type 2 diabetes mellitus. This association was still apparent after adjustment for confounding factors such as smoking exposure. Early life exposures that affect lung growth and insulin resistance are proposed to be catalysts for this eventual association later in life. There is evidence that independent risk factors for type 2 diabetes mellitus and atherosclerosis provide a common soil for the development of either one or both of these conditions. The insulin resistance syndrome is linked to both genetic and environmental causality. Evidence exists that links fetal and early postnatal nutritional stress resulting in low birth weight and low weight gain during the first year to later risk of insulin resistance, diabetes, or atherosclerotic disease.³⁶

Effects of corticosteroids on diabetes and COPD

The pathophysiology of COPD includes abnormal chronic airway and parenchymal inflammation in the lungs. Inflammatory cells accumulate in the walls of central airways. An acute increase in inflammation of this component can lead to an exacerbation of COPD.³⁷

A Cochrane meta-analysis identified 10 randomized controlled studies of the effect of systemic corticosteroids on various COPD outcomes, including length of hospital stay and rate of relapse.³⁸ The investigators reported a significant reduction in treatment failure in the first 30 days in corticosteroid-treated patients; it was necessary to treat 9 patients to avoid 1 treatment failure. FEV₁, PaO₂, PaCO₂, and dyspnea scores significantly improved in the first 72 hours, which may account for the decreased length of hospital stay reported in 2 studies.^39,40 However, mortality was not significantly different between patients who received corticosteroids and those who did not.

An increase in adverse effects in corticosteroid-treated patients was also found. However, a disparity in the incidence of adverse effects between the studies was likely secondary to the differences in the criteria to define an adverse effect. The effects varied from asymptomatic hyperglycemia to death. Thirteen patients would have to be treated to cause 1 case of hyperglycemia.³⁸

Erbland and associates⁴⁰ found that more patients in a corticosteroid group required treatment for hyperglycemia than in the placebo group; 67% of the corticosteroid-treated patients who required additional treatment for hyperglycemia had diabetes. Hyperglycemia was asymptomatic, and the two groups did not differ in the rate of onset of diabetes. This may reflect the relatively short course of corticosteroids used in trials designed to study acute exacerbations of COPD. Current recommendations are that a course of systemic corticosteroid treatment should be no longer than 14 days, because a longer course of therapy has not been shown to be beneficial.³⁸

In stable COPD, defined in most studies as a minimum of 4 weeks without acute exacerbation or use of systemic corticosteroids, short-term use of corticosteroids leads to statistically significant benefits in lung function, symptoms, and exercise capacity.⁴¹ These benefits occur at the cost of increased adverse events, such as osteoporosis, hyperglycemia, and suppression of the hypothalamic-pituitary-adrenal axis, and at doses that are unlikely to be safe for long-term use. Further study is needed to identify a subgroup of COPD patients in whom this benefit would outweigh the risks of long-term therapy.

CLINICAL OUTCOMES

Morbidity and mortality of diabetes and COPD

The in-hospital mortality of patients with acute exacerbations of COPD ranges from 4% to 30%.⁴² Impairment of lung function is associated with other comorbidities, such as cardiovascular disease, diabetes, and hypertension, leading to an increased risk of hospitalization and mortality.⁴³

Mannino and associates⁴³ conducted a study involving 20,296 persons who were 45 years or older at baseline and were participating in the Atherosclerosis Risk in Communities Study and the Cardiovascular Health Study. They stratified the patients according to baseline lung function using the modified Global Initiative for Chroinc Obstructive Lung Disease (GOLD) criteria. Then, they examined the prevalence of comorbid disease at baseline and death and hospitalizations during the 5 years of follow-up.

The authors reported more comorbid disease associated with lung function impairment. A logistic regression model that adjusted for age, ethnicity, sex, smoking, body mass index, and education revealed that in patients with GOLD stage 3 or 4 COPD, there was a higher prevalence of diabetes (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.1 - 1.9), hypertension (OR, 1.6; 95% CI, 1.3 - 1.9), and cardiovascular disease (OR, 2.4; 95% CI, 1.9 - 3.0). They concluded that the risk of hospitalization and mortality was increased with comorbid disease, which was worse in patients with impaired lung function.

In another study, Gudmundsson⁴⁴ showed that in 416 patients with an acute exacerbation of COPD prompting hospitalization, there was a relationship between older age, lower health status, decreased lung function, and diabetes. During the follow-up period of 24 months, 122 of the 416 patients (29.3%) died mainly of respiratory causes. The mortality rate was increased (hazard ratio, 2.25 [1.28 - 3.95]) among patients with diabetes and COPD. This study indicated that the mortality rate was higher in the presence of both diabetes and COPD.⁴⁴ A possible explanation for the worse outcomes of coexisting COPD and diabetes is that TNF-α, IL-6, and C-reactive protein levels are elevated in both disease states.⁴⁵

Hyperglycemia and critical care outcomes

A substantial body of literature has associated hyperglycemia with adverse clinical outcomes in patients with a variety of medical conditions, such as cardiovascular disease and stroke, and in postsurgical and trauma patients. In a study of more than 2000 patients admitted to the general hospital ward, Umpierrez and associates⁴⁶ demonstrated that newly discovered hyperglycemia on admission or during the hospital stay was associated with higher inpatient mortality than was the established diagnosis of diabetes.

In a study by van den Berghe,⁴⁷ 1548 mechanically ventilated patients in a surgical ICU (about 60% cardiac surgery) were randomized to receive continuous insulin infusion to maintain blood glucose levels of 80 to 110 mg/dL or standard control to keep the blood glucose level at 180 to 200 mg/dL. The intensive insulin infusion therapy reduced overall in-hospital mortality by 34%, ICU mortality by 43%, bacteremia by 46%, newly developed kidney failure requiring dialysis by 41%, critical illness polyneuropathy by 44%, and the number of red blood cell transfusions by 50%. The reduction in mortality was largely the result of a reduction in serious infections. It is important to note that only 13% of the patients in this study had a history of diabetes.⁴⁷

Krinsley⁴⁸ reported findings from a study that included 800 critically ill patients who were admitted to a medical-surgical ICU. Blood glucose levels were monitored before and after use of an insulin protocol to maintain plasma glucose values under 140 mg/dL. The use of intensive insulin-titrated glycemic control was associated with decreased length of stay in the ICU, a 29% reduction in hospital mortality, decreased incidence of new organ failure, and fewer blood transfusions.⁴⁸

In a study of 523 patients primarily undergoing cardiac surgery, Finney and colleagues⁴⁹ reported that glycemic control was responsible for the mortality benefit associated with intensive insulin therapy, not the higher amounts of insulin used. Insulin administration was positively correlated with death despite blood glucose values at the time.⁴⁹ Therefore, the mortality benefit was attributable to blood glucose levels and not the amount of insulin administered.

The association between glycemic control and improved outcomes in critical care may be the result of the anabolic effect of insulin on respiratory muscles, reduced osmotic diuresis, improved erythropoiesis, reduced hyperglycemic injury of neuronal axons, decreased cholestasis, and the anti-inflammatory associations of insulin.⁴⁸ Insulin is proved to be anti-inflammatory via inhibiting free fatty acids, inflammatory growth factors, and proinflammatory cytokines. Another direct benefit of insulin is that it enhances nitric oxide synthesis, which leads to vasodilation. Insulin also has a positive effect on the transcriptional factor, nuclear factor-κB, which controls proinflammatory cytokines, adhesion molecules, and chemokines.⁵⁰

Hyperglycemia and adverse outcomes in patients with COPD

Baker and colleagues⁹ retrospectively investigated the relationship between blood glucose and adverse outcomes in patients admitted for acute COPD exacerbation. Patients in the higher quartiles of blood glucose concentration were more likely to die or have a longer length of hospital stay. This finding was independent of age, sex, and prior diabetes. For each 1 mmol/L increase in blood glucose level, there was a 15% increase in the risk of adverse outcomes, even after adjustment for factors such as age and sex. Also, as the blood glucose level increased, there was an increase in the isolation of multiple pathogens and Staphylococcus aureus from the patients’ sputum.

Several potential mechanisms may explain the increased blood glucose levels and adverse clinical outcomes in COPD.⁹ In COPD, an increased blood glucose level may be a marker for more severe illness as a result of the metabolic effects of increased peripheral insulin resistance, elevated catecholamine levels, and raised glucocorticoid levels. Some of the hyperglycemia may be directly related to the corticosteroids used to treat an exacerbation of COPD. Clinical studies involving patients in ICUs or after myocardial infarction demonstrate an improvement in clinical outcome by reducing blood glucose levels. Regression analysis studies have demonstrated that it is the control of the blood glucose, not the insulin dose, that contributes to the clinical benefits.⁹ Other potential mechanisms may be the effects of oxidative stress and cellular glucose overload in acute illness, and the tendency toward infection as a result of local or systemic effects on bacterial growth or host immunity.

Studies have shown that tight glycemic control reduces hospital mortality and ICU length of stay in critically ill patients.⁴⁹ At this time, any special consideration for anticholinergic agents or β-agonists in patients with acute exacerbations of COPD and diabetes has not been well studied. In addition, further investigation is needed to establish whether glycemic control improves clinical outcomes in patients with exacerbations of COPD.

CONCLUSIONS

A significant relationship seems to exist between COPD and other comorbidities such as diabetes. It is likely that the mechanisms involved in pre-diabetes and diabetes may predispose patients to an earlier decline in lung function. Further studies are needed to examine whether patients with COPD and diabetes would benefit from tight glycemic control during routine care and/or during an acute exacerbation of COPD. Care of patients with COPD would be dramatically changed if good blood glucose control proved beneficial in reducing the mortality and morbidity of the disease.

References:

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