- Top of page
- PATIENTS AND METHODS
Glucocorticoids have been used for more than 50 years in a variety of diseases as potent antiinflammatory and immunosuppressive agents. It has been generally perceived that glucocorticoids adversely affect serum lipid levels (1), although study findings on the nature and extent of the effect vary substantially (2–9). Results of earlier cross-sectional studies based on organ transplant recipients suggested that glucocorticoid use was associated with adverse lipid profiles (elevated plasma triglyceride and total cholesterol levels) (2–7). However, the implicated causal link between glucocorticoid use and these adverse lipid profiles is potentially confounded by the variables that are themselves associated with corticosteroid use and possess known adverse effects on the lipid profile, such as disease status (e.g., uremia), physical activity levels, diet, and use of concomitant medications. Results of subsequent prospective studies have indicated that prednisone use actually improved lipid profiles (i.e., increased high-density lipoprotein [HDL] cholesterol, decreased total cholesterol:HDL cholesterol ratio, and insignificant change in triglyceride level) (8, 9).
The prevalence of glucocorticoid use increases with age in conjunction with the prevalence of indications for their use (e.g., obstructive pulmonary conditions and rheumatic conditions). Our weighted estimation based on the Third National Health and Nutritional Examination Survey (NHANES-III) data (10) demonstrated the prevalence of glucocorticoid use among persons ages 60 years or older was approximately twice that among persons younger than age 60 years. The disease indications for glucocorticoids also differ substantially between the age groups. Furthermore, with increasing age, the clinical consequences of an adverse lipid profile become more common.
To date, no published studies have examined the relationship between glucocorticoid use and lipid profiles in a representative sample of US adults. In this cross-sectional study based on the NHANES-III, we evaluated the relationship between glucocorticoid use and the serum lipid profile, stratified by age (age 60 years and older and age younger than 60 years).
- Top of page
- PATIENTS AND METHODS
Our objective was to evaluate the relationship between glucocorticoid use and serum lipid profile in a representative sample of US adults. In this study based on the NHANES-III, glucocorticoid users and nonusers younger than age 60 years had similar serum HDL cholesterol and total cholesterol levels and total cholesterol:HDL cholesterol ratios. However, among subjects 60 years of age or older, the serum HDL cholesterol level among glucocorticoid users was higher than that among nonusers, a finding that persisted in both sexes and different races. Meanwhile, there was only a minimal increase in the total cholesterol level, the magnitude of which was smaller than that of the HDL cholesterol level; thus, the ratio of total cholesterol:HDL cholesterol was significantly lower among glucocorticoid users in this population. Correspondingly, the serum Apo A-I level was significantly higher and the Apo A-I:Apo B ratio was lower among glucocorticoid users. The magnitudes of these favorable differences in the lipid profile were larger when we limited the glucocorticoids to prednisone only (i.e., more homogenous exposure). These associations were independent of age (within the group of subjects 60 years of age and older), education, smoking status, BMI, alcohol consumption, physical activity, intake of carbohydrates, fat, and total energy, and other potential confounders. These findings suggest that glucocorticoid use is not associated with an adverse lipid profile and may be associated with a favorable lipid profile in the population of individuals 60 years of age or older.
The magnitude of difference in the lipid profile among persons 60 years of age or older was clinically meaningful. For example, the 21% higher HDL cholesterol level associated with prednisone use is substantially better than the 8–10% increase with statins shown in clinical trials (15) and similar to that observed with nicotinic acid (20%) (16). The clinical relevance was further supported by the result of our analysis using HDL cholesterol cut-offs that predict coronary artery disease (13) (e.g., the odds of having a normal HDL cholesterol level was 4.7 times higher among prednisone users than among nonusers).
Our results in the older population closely agree with those of several previous studies based on prospective evaluation of a limited number of study subjects (8, 9). Zimmerman et al studied the effect of prednisone (mean dosage 47 mg/day at baseline, tapered to 20 mg/day at 1 month) and showed a 68% increase (22 mg/dl) in HDL cholesterol (P < 0.0001) at 1 month (8). The increase was already evident after 48 hours of prednisone therapy and persisted up to 18 months. Similar to the current study finding, the increase in the total cholesterol level was primarily attributable to the increase in the HDL cholesterol level, and no significant change in the LDL cholesterol and triglyceride levels was observed. Reflecting these changes, the ratio of LDL cholesterol:HDL cholesterol decreased (8). Similarly, Ettinger et al showed a 34% increase (17.8 mg/dl) in the HDL cholesterol level (P < 0.0001) after 1 month of prednisone therapy (60 mg at baseline tapered to 15 mg at 1 month), and the LDL cholesterol and triglyceride levels did not significantly change (9). Our results suggest that the findings from these prospective studies are generalizable to the population of individuals 60 years of age or older.
Although the mechanisms by which glucocorticoids may increase HDL cholesterol levels remain largely unknown, results of animal studies suggest that both synthesis and degradation of HDL cholesterol may be affected by glucocorticoids (8, 9). Glucocorticoids may stimulate hepatic production of HDL cholesterol (9, 17). Furthermore, glucocorticoids may enhance the activity of lipoprotein lipase or inhibit the activity of triglyceride lipase, 2 enzymes that are known to be important determinants of HDL cholesterol levels (8, 9, 18–20).
HDL cholesterol and Apo A-I levels are negatively correlated with disease activity in several rheumatologic disorders (21–26), including rheumatoid arthritis (25, 26) and systemic lupus erythematosus (22), as well as in other conditions associated with inflammation, such as acute infection (27) and lymphoma (28). In animal models, inflammation decreases the levels of HDL cholesterol and Apo A-I during the acute-phase response (29, 30). Because glucocorticoids are used in most of these chronic inflammatory disorders, it is conceivable that the potent antiinflammatory property of glucocorticoids may partly explain the observed positive association between glucocorticoid use and these lipid levels.
We observed an attenuated but significant similar trend in the relationship among persons receiving inhalation/intranasal glucocorticoids, but again, only in the older population. Because the systemic dose of glucocorticoid exposure is lower with this route of administration, these findings suggest that there may be a dose-response relationship between glucocorticoid use and HDL cholesterol effect. To our knowledge, no published studies have examined the relationship between these glucocorticoids and lipid profiles, although it has been increasingly recognized that inhaled corticosteroids have other systemic effects (e.g., suppression of the hypothalamic–pituitary–adrenal axis and association with osteoporosis, cataract, and glaucoma) (31, 32). The current finding suggests that there may be a beneficial effect on HDL cholesterol levels associated with these glucocorticoids in this older population.
We did not observe an adverse or beneficial effect on serum lipid levels associated with glucocorticoid use in the US population younger than age 60 years. Although these results suggest that the effect of glucocorticoids on the lipid profile differs between older and younger populations, there may be other potential explanations. Long-term users of systemic glucocorticoids who are younger are more often treated for disorders involving major organ dysfunction (e.g., transplant recipient) than those who are older. These disorders themselves tend to be associated with adverse lipid effects, confounding the relationship between glucocorticoid use and lipid levels, and may contribute to the overall null association. In this context, the indications for glucocorticoid therapy in the older population (e.g., polymyalgia rheumatica/elderly-onset rheumatoid arthritis, chronic obstructive lung disease) tend to be more homogeneous. Our attempt to address this issue was limited by the small sample size of each subgroup and the nonspecific ICD-9-CM coding of these data. However, when we repeated our analyses after further adjustment for potentially relevant variables or after eliminating those subjects with conditions potentially confounding the association, our results did not materially change. Furthermore, this potential explanation would be less applicable to the differential effect of inhalation/intranasal glucocorticoids on HDL cholesterol levels according to age group. Because the lack of dosing information in the NHANES-III prevented examining a potential dose effect of glucocorticoids on the lipid profile, the difference in glucocorticoid dose according to age group may explain the lipid profile differences. Last, other unmeasured factors associated with age may explain the apparent effect modification.
Although long-term use of high-dose glucocorticoids is associated with an unacceptable overall benefit-risk ratio in most clinical settings, in certain clinical settings there may be a dose of glucocorticoids that is low enough for the overall benefits to outweigh the overall risks, thereby providing a favorable therapeutic index (33–35). Although dose information is unavailable in these data, one may speculate that the systemic glucocorticoid dose in the older population tended to be low (≤10 mg of prednisone daily) (33), given their relatively long-term use of glucocorticoids. The attenuated but still favorable relationship between inhalation/intranasal glucocorticoid use and HDL cholesterol level in the older population also suggests a potential beneficial effect on the lipid profile from low-dose glucocorticoids. Prospective studies are warranted to examine these suggestions, because previous prospective studies showing improved lipid profiles used doses higher than low-dose at the time of lipid measurement. A favorable lipid profile resulting from low-dose glucocorticoid therapy could improve the therapeutic index (33–35) and raises intriguing implications for the inflammation paradigm of atherosclerosis (36). In addition, other potential metabolic effects of low-dose glucocorticoids (e.g., increasing adiposity, blood pressure, and insulin resistance) should be further investigated in future studies and incorporated into risk-benefit ratios in various clinical settings.
The strengths and limitations of our study deserve comment. This study was performed in a nationally representative sample of US women and men and race/ethnicity groups; thus, the findings are likely to be generalizable to the US population. A potential challenge associated with making causal inferences from highly generalizable data such as those from the NHANES-III may derive from the heterogeneity of its study participants. A larger difference in HDL cholesterol levels associated with glucocorticoid use shown in prospective studies (8, 9) suggests that the effect on lipid profile may be larger in certain more-homogenous subgroups. In addition, a cross-sectional study design tends to leave uncertainty regarding the temporal sequence of exposure–outcome relationships, but the NHANES-III health examination component (including serum lipid measurement) was performed after the household interview that inquired about prescription medication use during the past month. This means that the exposure (glucocorticoid use) preceded the outcome (serum lipid measures) in a way that is consistent with the methods of previous prospective studies of this association (8, 9). It remains unclear how much the presence of hyperlipidemia would affect a physician's decision to initiate or continue glucocorticoids when the medications are clinically indicated. However, its potential impact on our results appears minimal, given that there was no material change in our results after eliminating or adjusting for those taking lipid-lowering agents. Our analysis comprehensively adjusted for available potential confounding variables, including dietary variables; this was not feasible in most previous studies, likely due to a lack of such data or a smaller sample size.
In conclusion, our results suggest that glucocorticoid use is not associated with an adverse lipid profile in the US population and may be associated with a favorable lipid profile among persons 60 years of age or older, in concordance with previous prospective studies. These findings and other potential metabolic effects of glucocorticoid use (especially use of low-dose agents) should be further investigated in future studies and incorporated into risk-to-benefit ratios in various clinical settings.