SEARCH

SEARCH BY CITATION

Keywords:

  • Glucocorticoid;
  • Prednisone;
  • Corticosteroid;
  • Lipid profiles;
  • HDL-cholesterol;
  • Apolipoprotein A-I

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Objective

It has been generally perceived that glucocorticoids adversely affect serum lipid levels, although results of prospective studies have suggested the contrary. In this study, we sought to examine the relationship between glucocorticoid use and lipid profiles in a nationally representative sample of subjects.

Methods

Using data from 15,004 participants ages 20 years and older in The Third National Health and Nutrition Examination Survey (1988–1994), we examined the relationship between glucocorticoid use and serum lipid profiles. Glucocorticoid use was determined from the household interview regarding prescription medication use. We used multivariate linear regression to adjust for age, sex, race or ethnicity, education, smoking status, body mass index, physical activity, alcohol consumption, energy fraction from protein and carbohydrates, and total energy intake.

Results

Glucocorticoid use was associated with a higher serum high-density lipoprotein (HDL) cholesterol level and a lower ratio of total cholesterol-to-HDL cholesterol among subjects ages 60 years or older (multivariate difference 9.0 mg/dl [95% confidence interval (95% CI) 3.9, 14.1] and −0.6 mg/dl [95% CI −0.9, −0.3], respectively) but not among those younger than age 60 years (multivariate difference −1.5 mg/dl [95% CI −5.4, 2.5] and 0.1 mg/dl [95% CI −0.3, 0.5], respectively). Correspondingly, glucocorticoid use was associated with a higher serum apolipoprotein A-I (Apo A-I) level and a lower Apo A-I:Apo B ratio (multivariate difference 12.1 mg/dl [95% CI 2.9, 21.3] and 0.16 mg/dl [95% CI 0.03, 0.29], respectively) only among subjects ages 60 years or older. Inhalation/intranasal glucocorticoid use was also associated with a higher serum HDL cholesterol level (multivariate difference 4.9 mg/dl [95% CI 0.3, 9.5]) only among subjects ages 60 years or older.

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 ages 60 years or older, in concordance with previous prospective studies.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

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).

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Study population

Conducted between 1988 and 1994, NHANES-III included a representative sample of the noninstitutionalized US civilian population, which was selected using a multistage, stratified sampling design. Persons 60 years of age and older and African American and Mexican American persons were oversampled. After a home interview (n = 33,994), participants were invited to attend examination sessions (n = 30,818), during which blood and urine specimens were obtained. We limited our primary analyses to 4,727 adults (2,308 men and 2,419 women) 60 years of age or older (older group) and 10,277 adults (4,721 men and 5,556 women) ages 20–60 years (younger group) who attended the medical examination and had complete information on HDL cholesterol, total cholesterol, and covariates of our analyses. Other lipid markers (i.e., apolipoprotein [Apo] A-I and Apo B, and lipoprotein[a] levels, triglyceride level after a fast of ≥8 hours, and the low-density lipoprotein [LDL] cholesterol level among subjects with a triglyceride levels ≤400 mg/dl) were available for fewer participants. Thus, analyses for these other markers used the maximum number of subjects available for each lipid marker and covariates.

Lipid profile measurement

The levels of serum HDL cholesterol, total cholesterol, and triglycerides were measured enzymatically (Hitachi 704 Analyzer; Boehringer Mannheim Diagnostics, Indianapolis, IN). The serum LDL cholesterol concentration was calculated using the Friedewald equation (i.e., LDL = total cholesterol − high density cholesterol − triglyceride/5). Apo A-I and Apo B levels were measured by nephelometry (Beckman Instruments, Brea, CA). Lipoprotein(a) levels were measured using an enzyme-linked immunosorbent assay kit (Strategic Diagnostics, Newark, DE). Details of the laboratory procedures involved in these measurements, including quality control, have been published elsewhere (11). Lipid levels are reported in milligrams per deciliter (to convert to millimoles per liter, multiply by 0.02586).

Assessment of glucocorticoid use

During the household interview, respondents were asked: Have you taken or used any medicines for which a doctor's or dentist's prescription is needed, in the past month? For each medication reported, the interviewer asked to see the medication container to record the product name. If the container was unavailable, the interviewer queried the subject for this information. Each prescription drug reported in the survey was subsequently identified in the Physicians GenRx (12), and assigned a standard generic name and 4-digit generic code for that product. Up to 3 drug class codes based on the National Drug Code Directory prepared by the Product Information Management Branch of the US Food and Drug Administration were assigned to each prescription medication that a respondent reported. The health problem respondents described as the reason for taking the prescription medicine was classified by the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) codes. No information on the dosage of prescription medication was collected. The oral glucocorticoids reported by NHANES-III participants consisted of prednisone, prednisolone, methylprednisolone, betamethasone, and triamcinolone. Of these glucocorticoids, prednisone accounted for ∼90% of the use. Inhalation/intranasal glucocorticoids reported by NHANES-III participants consisted of beclomethasone, dexamethasone, flunisolide, and triamcinolone.

Assessment of covariates

In NHANES-III, information on demographic data, education, smoking status, and body measurements (including height and weight) was collected. The body mass index (BMI) was recorded as weight in kilograms divided by height in meters squared (kg/m2). Respondents were asked how often during the past month they had participated in 9 specified and 4 other leisure-time physical activities, from which we calculated a physical activity index by summing the products of the frequency of participation and the metabolic equivalent level for each reported activity. Alcohol consumption was determined from responses to a food frequency questionnaire. The energy fraction from protein, fat, carbohydrates, and the total energy intake was calculated from a single 24-hour dietary recall.

Statistical analysis

All statistical analyses were performed using survey commands of STATA (e.g., SVYMEAN and SVYREG) to incorporate sample weights and adjust for clusters and strata of the complex sample design (version 8; STATA Corporation, College Station, TX). Means or percentages for characteristics were calculated according to glucocorticoid use, stratified by age group.

We used linear regression to evaluate relationships between glucocorticoid use and serum lipid levels. Multivariate models were adjusted for age, sex, race or ethnicity (white, African American, Mexican American, or other), education (years of school attendance), smoking status (current, former, or never), BMI, alcohol consumption (number of drinks per month), physical activity (5 categories), energy fraction from protein and carbohydrates, and total energy intake. We also performed logistic regression to evaluate relationships between glucocorticoid use and a dichotomous HDL cholesterol level variable (normal HDL cholesterol level [>37 mg/dl] versus a low level [≤37 mg/dl] among men; normal HDL cholesterol level [>47 mg/dl] versus a low level [≤47 mg/dl] among women) (13) and the total cholesterol:HDL cholesterol ratio variable (normal ratio [<5] versus high ratio [≥5]), adjusting for the same covariates.

We explored potential interactions according to age group (age ≥60 years versus age <60 years), sex, BMI (<25 kg/m2 versus ≥25 kg/m2), or race (non-Hispanic white versus the other race groups) by testing the significance of the interaction terms added to our final multivariate models. For all effect measures, we calculated 95% confidence intervals (95% CIs). All P values are 2-sided. The sample sizes for our primary analyses were sufficient, exceeding the recommended minimal sample size, but those for most exploratory subgroup analyses were not (14). We indicated these small subgroups where applicable, as recommended by the Analytic and Reporting guideline of NHANES-III (14).

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Glucocorticoid use in the NHANES-III

The prevalence of glucocorticoid use in persons 60 years of age or older in the US was 1.7% (95% CI 1.3, 2.1%), and in those younger than age 60 years it was 0.9% (95% CI 0.6, 2.6%). Overall, among subjects 60 years of age or older, 39% of the use was for rheumatic or dermatologic disorders, 34% was for pulmonary disorders, 23% was for other indications, and 4% had no listed indication. Among persons younger than age 60 years, 23% of glucocorticoid use was for rheumatic or dermatologic disorders, 14% was for pulmonary disorders, 60% was for other indications, and 4% had no listed indication. The mean duration of glucocorticoid use in the older age group was 45 months (95% CI 26, 64), with 80% of use for >1 month, while in the younger age group the mean disease duration was 20 months (95% CI 9, 32), with 64% of use for >1 month.

Characteristics according to glucocorticoid use

Characteristics of the US population according to prednisone use are summarized, stratified by age group, in Table 1. Overall, glucocorticoid users tended to be older and less active and drank less alcohol compared with nonusers. In addition, there were more past smokers and fewer current smokers among glucocorticoid users. Among subjects younger than age 60 years, glucocorticoid users were more often female and white (Table 1).

Table 1. Patient characteristics according to GC use*
CharacteristicAge <60 yearsAge ≥60 years
GCs (n = 76)No GCs (n = 10,201)GCs (n = 81)No GCs (n = 4,646)
  • *

    Values are the mean ± SD. Antilipemic agents included colestipol, cholestyramine, clofibrate, gemfibrozil, and probucol. Statins included lovastatin, pravastatin, and simvastatin. GC = glucocorticoid.

Age, years40.9 ± 1.737.2 ± 0.272.5 ± 1.270.5 ± 0.2
Men, %37.8 ± 9.349.1 ± 0.647.4 ± 8.742.7 ± 0.8
White, %84.2 ± 3.274.6 ± 1.488.8 ± 3.885.5 ± 1.3
Education, years12.3 ± 0.313.1 ± 0.113.2 ± 2.011.5 ± 0.2
Current smoker, %25.0 ± 6.832.3 ± 0.13.0 ± 2.314.7 ± 0.9
Past smoker, %41.4 ± 10.021.8 ± 0.161.1 ± 6.439.5 ± 1.2
Body mass index, kg/m226.9 ± 1.126.4 ± 0.127.7 ± 0.626.9 ± 0.1
Inactive, %19.2 ± 6.212.8 ± 0.840.1 ± 8.421.1 ± 1.3
Alcohol intake, servings/day0.09 ± 0.040.30 ± 0.010.20 ± 0.070.26 ± 0.02
Total energy intake, kcal2,300 ± 2412,328 ± 221,737 ± 1061,724 ± 17
Carbohydrate intake, % of energy47.0 ± 1.549.2 ± 0.352.7 ± 1.451.8 ± 0.3
Fat intake, % of energy38 ± 1.734 ± 0.332 ± 1.132 ± 0.2
Antilipemic agent use, %4.4 ± 4.11.3 ± 0.22.8 ± 1.96.2 ± 0.6
Statin use, %4.4 ± 4.10.8 ± 0.10.3 ± 0.32.9 ± 0.5
Diabetes, %7.1 ± 4.43.4 ± 0.211.0 ± 4.312.2 ± 0.6
Thyroid disease, %3.8 ± 2.33.3 ± 0.38.4 ± 3.67.8 ± 0.5

HDL cholesterol and total cholesterol levels according to glucocorticoid use

The association between glucocortoid use and HDL cholesterol or the total cholesterol:HDL cholesterol ratio significantly differed according to age group (i.e., age ≥60 years versus age <60 years; P for interaction 0.003 and 0.001, respectively). HDL cholesterol, total cholesterol, or the total cholesterol:HDL cholesterol ratio was not associated with glucocorticoid use among persons younger than age 60 years (Table 2).

Table 2. Mean serum lipid levels according to use of oral GCs*
Lipid/analysisAge <60 yearsAge ≥60 years
GCs (n = 76)No GCs (n = 10,201)Difference (95% CI)GCs (n = 81)No GCs (n = 4,646)Difference (95% CI)
  • *

    Multivariate analyses were adjusted for age, sex, race/ethnicity, education (years attending school), smoking status (current, former, never), body mass index, alcohol consumption (number of drinks per month), physical activity (5 categories), energy fraction from protein and carbohydrates, and total energy intake. GCs = glucocorticoids; 95% CI = 95% confidence interval; HDL-C = high-density lipoprotein cholesterol.

HDL-C, mg/dl      
 Crude49.850.5−0.7 (−5.4, 4.0)59.151.47.6 (2.1, 13.2)
 Age-adjusted49.950.6−0.6 (−5.3, 4.0)59.051.57.5 (2.0, 13.0)
 Multivariate49.751.2−1.5 (−5.4, 2.5)60.251.29.0 (3.9, 14.1)
Total cholesterol, mg/dl      
 Crude207.0198.68.4 (−10.8, 27.6)230.7224.06.6 (−4.0, 17.3)
 Age-adjusted201.5198.03.5 (−14.1, 21.1)230.9223.57.5 (−3.4, 18.3)
 Multivariate201.0198.03.1 (−14.4, 20.5)228.8220.97.9 (−2.7, 18.4)
Total cholesterol:HDL-C      
 Crude4.54.30.2 (−0.3, 0.7)4.24.8−0.6 (−0.9, −0.3)
 Age-adjusted4.34.30.1 (−0.4, 0.5)4.24.8−0.5 (−0.8, −0.2)
 Multivariate4.34.30.1 (−0.3, 0.5)4.14.7−0.6 (−0.9, −0.3)

Among persons 60 years of age or older, glucocorticoid use was associated with a 15% higher unadjusted mean serum HDL cholesterol level compared with no use (a difference of 7.6 mg/dl [95% CI 2.1, 13.2]) (Table 2 and Figure 1). After adjusting for age, sex, race or ethnicity, education, smoking status, BMI, alcohol intake, physical activity, energy fraction from fat and carbohydrates, and total energy intake, the difference was larger (18%; 9.0 mg/dl [95% CI 3.9, 14.1]). The difference was 11.3 mg/dl (95% CI 3.4, 19.2) for glucocorticoid use for 1 month or less and 8.3 mg/dl (95% CI 2.3, 14.4) for use longer than 1 month. When we limited glucocorticoid exposure to prednisone only, the differences were even larger (a difference of 9.2 mg/dl [95% CI 3.2, 15.0]) (Figure 1). The difference for glucocorticoid use for rheumatologic conditions tended to be larger than that for other conditions (a difference of 12.6 mg/dl [95% CI −1.7, 26.9] versus 7.7 mg/dl [95% CI 3.3, 12.1]). Correspondingly, in this age group, glucocorticoid use was associated with a normal HDL level (dichotomously defined by >37 mg/dl among men and >47 mg/dl among women &lsqbr;13&rsqbr;) (multivariate odds ratio [OR] 3.7 [95% CI 2.0, 6.6]).

thumbnail image

Figure 1. High-density lipoprotein cholesterol (HDL-C) levels according to glucocorticoid use among men and women 60 years of age or older. HDL-C levels were adjusted for age, race/ethnicity, education (years of school attendance), smoking status (current, former, or never), body mass index, alcohol consumption (number of drinks per month), physical activity (5 categories), energy fraction from protein and carbohydrates, and total energy intake. P values are from multivariate linear regression models after adjusting for these covariates as compared with no use. The sample size for inhalation/intranasal (Inh.) glucocortocoids, stratified by sex, was smaller than the sample size recommended by the Analytic and Reporting guideline of the Third National Health and Nutritional Examination Survey (14). Bars show the mean ± SEM.

Download figure to PowerPoint

Among subjects 60 years of age or older, the increase in HDL cholesterol concentration with glucocorticoid use was observed in both sexes, and the magnitude of increase was similar (multivariate difference 8.7 mg/dl [95% CI 2.3, 15.0] among men and 9.2 mg/dl [95% CI 1.5, 16.9] among women; P for interaction 0.92) (Figure 1). Similarly, the increase in HDL cholesterol concentration with prednisone use was observed among different race/ethnic groups (Figure 2) and was not significantly different between non-Hispanic white participants and the other participants in this age group (P for interaction 0.56). There was no significant effect modification by BMI (<25 kg/m2 versus ≥25 kg/m2; P for interaction 0.73).

thumbnail image

Figure 2. HDL cholesterol levels according to glucocorticoid use among men and women 60 years of age or older of different racial/ethnic groups. HDL cholesterol levels were adjusted as described in Figure 1. P values are from multivariate linear regression models after adjusting for these covariates as compared with no use. The sample sizes for exposed non-white groups were smaller than the sample size recommended by the Analytic and Reporting guideline of the Third National Health and Nutritional Examination Survey (14). Bars show the mean ± SEM. See Figure 1 for definitions.

Download figure to PowerPoint

Among persons 60 years of age or older, the mean total cholesterol levels did not differ according to glucocorticoid or prednisone use. Adjustment for covariates did not materially change the results (Table 2). Thus, the total cholesterol:HDL cholesterol ratio was significantly lower among glucocorticoid or prednisone users than among nonusers (multivariate difference −0.6 [95% CI −0.9, −0.3] versus −0.8 [95% CI −1.1, −0.4]) (Table 2). The difference in lipoprotein ratio for glucocorticoid use for rheumatologic conditions was similar to that for other conditions (difference −0.6 [95% CI −1.2, −0.0] versus −0.6 [95% CI −1.0, −0.2]). Correspondingly, in this age group, glucocorticoid use was associated with a normal total cholesterol:HDL cholesterol ratio (dichotomously defined by <5; multivariate OR 2.2 [95% CI 1.04, 4.6]).

HDL cholesterol and total cholesterol levels according to inhalation/intranasal glucocorticoid use

Among persons 60 years of age or older, inhalation/intranasal glucocorticoid use was associated with a 10% higher serum HDL cholesterol level compared with no use (multivariate difference 4.9 mg/dl [95% CI 0.3, 9.5]) (Figure 1). However, no association was observed among persons younger than age 60 years (multivariate difference in HDL cholesterol levels 0.3 mg/dl [95% CI −3.5, 4.1]). There was no significant association with total cholesterol levels or the total cholesterol:HDL cholesterol ratio in either age group.

Other lipid levels according to glucocorticoid use

Among subjects 60 years of age or older, oral glucocorticoid use was associated with an 8% higher adjusted mean serum Apo A-I level compared with no use (multivariate difference 12.1 mg/dl [95% CI 2.9, 21.3]) (Figure 3). After limiting glucocorticoid use to prednisone, the difference was larger (multivariate difference 10%; 14.5 mg/dl [95% CI 4.9, 24.1]). Apo B levels did not significantly differ according to glucocorticoid or prednisone use; thus, the Apo A-I:Apo B ratio was significantly higher among glucocorticoid or prednisone users than among nonusers in this older age group (multivariate difference 0.16 [95% CI 0.03, 0.29]) (Figure 3). There was no significant association between glucocorticoid use and these lipid markers among persons younger than 60 years of age. There was no significant association between glucocorticoid use and other lipid marker levels (Figure 3).

thumbnail image

Figure 3. Lipid levels according to glucocorticoid use among men and women 60 years of age or older. Lipid levels were adjusted as described in Figure 1. P values are from multivariate linear regression models after adjusting for these covariates as compared with no use. The sample sizes of the exposed groups were smaller than the sample size recommended by the Analytic and Reporting guideline of the Third National Health and Nutritional Examination Survey (14). LDL-C = low-density lipoprotein cholesterol; Inh. = inhalation/intranasal. Bars show the mean ± SEM.

Download figure to PowerPoint

Additional multivariate analyses

When we further adjusted for additional potential confounders in our multivariate models (i.e., self-reported physician-diagnosed thyroid disorders, diabetes, and lupus; aspartate aminotransferase levels as a surrogate for liver disorders; serum creatinine as a surrogate for renal disorders; hormone replacement therapy; and lipid-lowering agent use) our results did not materially change. For example, among persons 60 years of age or older, after additionally adjusting for all of these variables, the difference in HDL cholesterol levels according to glucocorticoid use was 9.0 mg/dl (95% CI 4.0, 14.0) and the difference in the total cholesterol:HDL cholesterol ratio was −0.7 (95% CI −1.0, −0.3). The corresponding OR for a normal HDL cholesterol level was 3.8 (95% CI 2.1, 6.8) and that for a normal total cholesterol:HDL cholesterol ratio was 2.3 (95% CI 1.0, 5.1). Similarly, when we repeated our analyses after eliminating subjects with these conditions (thyroid disorders, diabetes, lupus, serum creatinine level >1.5 mg/dl, abnormal aspartate aminotransferase level, hormone replacement therapy, or lipid-lowering agent use) one at a time, our results did not materially change.

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

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.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. PATIENTS AND METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
  • 1
    Maxwell SR, Moots RJ, Kendall MJ. Corticosteroids: do they damage the cardiovascular system? Postgrad Med J 1994; 70: 86370.
  • 2
    Bagdade J, Casaretto A, Albers J. Effects of chronic uremia, hemodialysis, and renal transplantation on plasma lipids and lipoproteins in man. J Lab Clin Med 1976; 87: 3848.
  • 3
    Cattran DC, Steiner G, Wilson DR, Fenton SA. Hyperlipidemia after renal transplantation: natural history and pathophysiology. Ann Intern Med 1979; 91: 5549.
  • 4
    Ibels LS, Alfrey AC, Weil R 3rd. Hyperlipidemia in adult, pediatric and diabetic renal transplant recipients. Am J Med 1978; 64: 63442.
  • 5
    Savdie E, Gibson JC, Stewart JH, Simons LA. High-density lipoprotein in chronic renal failure and after renal transplantation. Br Med J 1979; 1: 92830.
  • 6
    Broyer M, Tete MJ, Laudat MH, Goldstein S. Plasma lipids in kidney transplanted children and adolescents: influence of pubertal development, dietary intake and steroid therapy. Eur J Clin Invest 1981; 11: 397402.
  • 7
    Galla JH, Curtis JJ, Woodford SY, Rees ED, Somes GW, Luke RG. Effect of prednisone dose spacing on plasma lipids. J Lab Clin Med 1980; 95: 8017.
  • 8
    Zimmerman J, Fainaru M, Eisenberg S. The effects of prednisone therapy on plasma lipoproteins and apolipoproteins: a prospective study. Metabolism 1984; 33: 5216.
  • 9
    Ettinger WH, Klinefelter HF, Kwiterovitch PO. Effect of short-term, low-dose corticosteroids on plasma lipoprotein lipids. Atherosclerosis 1987; 63: 16772.
  • 10
    US Department of Health and Human Services (DHHS). National Center for Health Statistics. Third national health and nutrition examination survey, 1988–1994, NHANES III prescription medicines data file documentation (CD-ROM, Series 11, No. 2A). Hyattsville (MD): Centers for Disease Control and Prevention; 1998.
  • 11
    Centers for Disease Control and Prevention. NHANES III 1988–94 reference manuals and reports (CD-ROM). Hyattsville (MD): National Center for Health Statistics; 1996.
  • 12
    Denniston PL Jr, Epner JA. Physicians GenRx, 1994, The Official Drug Reference. Smithtown (NY): Data Pharmaceutica; 1993.
  • 13
    American Heart Association. Heart disease and stroke statistics: 2003 update. Dallas (TX): American Heart Association; 2002. p. 29.
  • 14
    Center for Health Statistics. Analytic and reporting guidelines: the Third National Health and Nutrition Examination Survey, NHANES III, 1988–94 National Center for Health Statistics. Vol. 32. Centers for Disease Control and Prevention. 1996 October. p. 147.
  • 15
    Blumenthal RS. Statins: effective antiatherosclerotic therapy. Am Heart J 2000; 139: 57783.
  • 16
    Martin-Jadraque R, Tato F, Mostaza JM, Vega GL, Grundy SM. Effectiveness of low-dose crystalline nicotinic acid in men with low high-density lipoprotein cholesterol levels. Arch Intern Med 1996; 156: 10818.
  • 17
    Shen BW, Scanu AM, Kezdy FJ. Structure of human serum lipoproteins inferred from compositional analysis. Proc Natl Acad Sci U S A 1977; 74: 83741.
  • 18
    Fainaru M, Havel RJ, Imaizumi K. Radioimmunoassay of arginine-rich apolipoprotein of rat serum. Biochim Biophys Acta 1977; 490: 14455.
  • 19
    Havel RJ, Eder HA, Bragdon JH. The distribution and chemical composition of ultracentrifugally separated lipoproteins in human serum. J Clin Invest 1955; 34: 134553.
  • 20
    Mahley RW, Innerarity TL, Bersot TP, Lipson A, Margolis S. Alterations in human high-density lipoproteins, with or without increased plasma-cholesterol, induced by diets high in cholesterol. Lancet 1978; 2: 8079.
  • 21
    Cabana VG, Gidding SS, Getz GS, Chapman J, Shulman ST. Serum amyloid A and high density lipoprotein participate in the acute phase response of Kawasaki disease. Pediatr Res 1997; 42: 6515.
  • 22
    Borba EF, Santos RD, Bonfa E, Vinagre CG, Pileggi FJ, Cossermelli W, et al. Lipoprotein(a) levels in systemic lupus erythematosus. J Rheumatol 1994; 21: 2203.
  • 23
    Orem A, Deger O, Memis O, Bahadir S, Ovali E, Cimsit G. Lp(a) lipoprotein levels as a predictor of risk for thrombogenic events in patients with Behcet's disease. Ann Rheum Dis 1995; 54: 7269.
  • 24
    Chou CT, Chao PM. Lipid abnormalities in Taiwan aborigines with gout. Metabolism 1999; 48: 1313.
  • 25
    Park YB, Choi HK, Kim MY, lee WK, Song J, Kim DK, et al. Effects of antirheumatic therapy on serum lipid levels in patients with rheumatoid arthritis: a prospective study. Am J Med 2002; 113: 18893.
  • 26
    Park YB, Lee SK, Lee WK, Suh CH, Lee CW, Lee CH, et al. Lipid profiles in untreated patients with rheumatoid arthritis. J Rheumatol 1999; 26: 17014.
  • 27
    Gidding SS, Stone NJ, Bookstein LC, Laskarzewski PM, Stein EA. Month-to-month variability of lipids, lipoproteins, and apolipoproteins and the impact of acute infection in adolescents. J Pediatr 1998; 133: 2426.
  • 28
    Blackman JD, Cabana VG, Mazzone T. The acute-phase response and associated lipoprotein abnormalities accompanying lymphoma. J Intern Med 1993; 233: 2014.
  • 29
    Cabana VG, Lukens JR, Rice KS, Hawkins TJ, Getz GS. HDL content and composition in acute phase response in three species: triglyceride enrichment of HDL a factor in its decrease. J Lipid Res 1996; 37: 266274.
  • 30
    Hosoai H, Webb NR, Glick JM, Tietge UJ, Purdom MS, de Beer FC, et al. Expression of serum amyloid A protein in the absence of the acute phase response does not reduce HDL cholesterol or apoA-I levels in human apoA-I transgenic mice. J Lipid Res 1999; 40: 64853.
  • 31
    Israel E, Banerjee TR, Fitzmaurice GM, Kotlov TV, LaHive K, LeBoff MS. Effects of inhaled glucocorticoids on bone density in premenopausal women. N Engl J Med 2001; 345: 9417.
  • 32
    Cumming RG, Mitchell P, Leeder SR. Use of inhaled corticosteroids and the risk of cataracts. N Engl J Med 1997; 337: 814.
  • 33
    Pincus T, Sokka T, Stein CM. Are long-term very low doses of prednisone for patients with rheumatoid arthritis as helpful as high doses are harmful? Ann Intern Med 2002; 136: 768.
  • 34
    Van Everdingen AA, Jacobs JW, Siewertsz van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med 2002; 136: 112.
  • 35
    Bae SC, Corzillius M, Kuntz KM, Liang MH. Cost-effectiveness of low dose corticosteroids versus non-steroidal anti-inflammatory drugs and COX-2 specific inhibitors in the long-term treatment of rheumatoid arthritis. Rheumatology (Oxford) 2003; 42: 4653.
  • 36
    Ross R. Atherosclerosis: an inflammatory disease. N Engl J Med 1999; 340: 11526.