Li Wei, MB, MSc; Thomas M. MacDonald, MD, FRCPE; Brian R. Walker, MD, FRCPE
Acknowledgments: The MEMO database is part of the U.K. Medical Research Council Health Services Research Collaboration.
Grant Support: By the Chief Scientist Office of the Scottish Executive (research grant CZG/4/1/36). Dr. Walker is a British Heart Foundation Senior Research Fellow.
Potential Financial Conflicts of Interest: Expert testimony: T.M. MacDonald (U.K. Committee on Safety of Medicines).
Requests for Single Reprints: Thomas M. MacDonald, MD, FRCPE, Medicines Monitoring Unit, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, United Kingdom; e-mail, email@example.com.
Current Author Addresses: Drs. Wei and MacDonald: Medicines Monitoring Unit, Division of Medicine and Therapeutics, Ninewells Hospital and Medical School, Dundee, Scotland DD1 9SY, United Kingdom.
Dr. Walker: University of Edinburgh, Endocrinology Unit, School of Molecular and Clinical Medicine, Western General Hospital, Edinburgh, Scotland EH4 2XU, United Kingdom.
Author Contributions: Conception and design: L. Wei, T.M. MacDonald, B.R. Walker.
Analysis and interpretation of the data: L. Wei, T.M. MacDonald, B.R. Walker.
Drafting of the article: L. Wei, T.M. MacDonald, B.R. Walker.
Critical revision of the article for important intellectual content: L. Wei, T.M. MacDonald, B.R. Walker.
Final approval of the article: L. Wei, T.M. MacDonald, B.R. Walker.
Provision of study materials or patients: L. Wei, T.M. MacDonald.
Statistical expertise: L. Wei, T.M. MacDonald.
Obtaining of funding: L. Wei, T.M. MacDonald, B.R. Walker.
Administrative, technical, or logistic support: L. Wei, T.M. MacDonald.
Collection and assembly of data: L. Wei, T.M. MacDonald.
Wei L., MacDonald T., Walker B.; Taking Glucocorticoids by Prescription Is Associated with Subsequent Cardiovascular Disease. Ann Intern Med. 2004;141:764-770. doi: 10.7326/0003-4819-141-10-200411160-00007
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Published: Ann Intern Med. 2004;141(10):764-770.
Patients who take glucocorticoids appear to have an increased risk for cardiovascular disease. However, data about the magnitude of this increased risk are lacking
In this large, population-based study, the use of glucocorticoids was associated with an increased risk for cardiovascular events, with a clear dose-response relationship. Patients who received high-dose glucocorticoids were more than 2.5 times as likely as patients who did not use glucocorticoids to experience a cardiovascular event.
These data will help clinicians estimate cardiovascular risk among patients who require glucocorticoids.
Glucocorticoids are commonly used as anti-inflammatory and immunosuppressive therapy in diseases such as asthma, inflammatory bowel disease, and inflammatory arthritis. Well-known adverse effects of glucocorticoids include hypertension, diabetes mellitus, and obesity (1-3), all of which are independent risk factors for cardiovascular disease. The principal physiologic glucocorticoid is cortisol. Increased cortisol secretion and action, even within the “physiologic” range, is associated with several risk factors for cardiovascular disease (4, 5). Indeed, studies have proposed that subclinical Cushing syndrome may be an important cardiovascular risk factor (6, 7). However, whether, and to what extent, the adverse effects of exogenous glucocorticoids on these risk factors for cardiovascular disease cause cardiovascular morbidity and death has not been established (8, 9). This is not predictable, especially since glucocorticoids may also have cardioprotective effects mediated by their anti-inflammatory and antiproliferative actions in the vessel wall (10, 11).
Allan C Gelber
Johns Hopkins University School of Medicine
December 16, 2004
A Rheumatology Perspective
The relationship of steroid therapy to risk of cardiovascular disease is of great interest, particularly among rheumatologists. Notably, systemic lupus erythematosus and rheumatoid arthritis are each linked to an increased incidence of heart disease and stroke (1) (2) (3) (4). These observations spark ongoing debate as to whether the offending process is the disease itself or the drug(s), particularly steroids, used to treat the disease.
In this context , the recent paper by Wei, MacDonald and Walker (5) tested the hypothesis that users of exogenous glucocorticoids have an increased risk for cardiovascular disease. The investigators studied this association using an administrative database. All dispensed community prescriptions, in a geographical population in Scotland numbering 400,000 people, were linked with hospital discharge and mortality data.
The number of participants with inflammatory arthritis, however, was relatively small, and constituted only 1.7% of the 68,781 glucocorticoid users. Moreover, the range of steroid doses in the "high" exposure category was ostensibly rather broad. For example, among patients treated for active giant cell arteritis, lupus nephritis or even polymyalgia rheumatica, a common starting dose of prednisone is 1 mg/kg/day. This often corresponds to average steroid exposures during the first year of therapy at substantially higher levels than the cutoff for the high exposure category, of > 7.5 mg of prednisolone per day. Therefore, even though patients with inflammatory arthritis were captured in the dataset, the richness of the data beyond the upper cutoff is seemingly not fully captured. One remains intrigued to know if the observed dose-response relationship would similarly apply, and perhaps be amplified, among those with active rheumatologic disorders.
In the same vein, an important limitation is the lack of clear information regarding inpatient steroid administration. Many patients with severe and life-threatening rheumatic disorders are often treated as inpatients with corticosteroids administered at pulse levels, with 1000 mg of methylprednisolone for several consecutive days. Information regarding exposure to these levels is again not captured.
Finally, the number of Scottish residents in the high level category constituted only 2% of the Exposure Cohort. Interestingly, it was the high dose group among those with Inflammatory Arthritis who experienced a 5- fold increase in cardiovascular risk, the highest risk estimate reported. Yet, it remains plausible that the severity of disease activity in these patients, rather than their therapy, was the causative factor for this high risk, and that steroids may have actually attenuated rather than exacerbated their risk.
(1) Manzi S, Meilahn EN, Rairie JE, Conte CG, Medsger TA, Jr., Jansen-McWilliams L et al. Age-specific incidence rates of myocardial infarction and angina in women with systemic lupus erythematosus: comparison with the Framingham Study. Am J Epidemiol 1997; 145(5):408-415.
(2) Solomon DH, Karlson EW, Rimm EB, Cannuscio CC, Mandl LA, Manson JE et al. Cardiovascular morbidity and mortality in women diagnosed with rheumatoid arthritis. Circulation 2003; 107(9):1303-1307.
(3) Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994; 37(4):481-494.
(4) Sibley JT, Olszynski WP, Decoteau WE, Sundaram MB. The incidence and prognosis of central nervous system disease in systemic lupus erythematosus. J Rheumatol 1992; 19(1):47-52.
(5) Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141(10):764-770.
Victor M Martinez-Taboada
Rheumatology Division. Hospital Universitario MarquÂ¨Â¦s de Valdecilla.
January 29, 2005
Increase in homocysteine levels: a new atherogenic mechanism of corticosteroids
To the Editor
We read with interest the study recently published in Annals of Internal Medicine by Wei L and co-investigators (1). In this large cohort study, the use of corticosteroids was associated with an increased risk for cardiovascular events, especially in patients treated with high-dose corticosteroids (Â¡Ã 7.5 mg of prednisone or equivalent). These results are also consistent with another case-control study, which demonstrated that higher doses of corticosteroids were more prevalent in patients with cardiovascular disease (2). After correction for confounder factors such as underlying disease or other well-known vascular risk factors of steroid use (blood pressure, glucose and lipids), the authors found no significant influence of them of the main results of the study.
In 2003, our group described several findings on patients with polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) during corticosteroid treatment (3). First, patients with active PMR and GCA had a significant elevation of homocysteine levels compared with age-matched controls. A non-surprising observation because previous studies have suggested that GCA may share a common pathway with atherosclerosis (4). Second, The increase in homocysteine levels was also not related to the inflammatory process per se. In fact, we found a negative correlation between acute-phase response and homocysteine levels in the GCA group. Third, and more interesting, treatment with corticosteroids induced an increase in homocysteine levels in both groups of patients. However, this increase was only significant in patients with GCA. In our daily practice, PMR patients are usually treated with 10 mg of prednisone, and GCA patients are treated with 45 to 60 mg of prednisone or equivalent. Thus, our results might reflect that the higher increase in homocysteine levels seen in patients with GCA is due to the higher doses of corticosteroids used to treat these patients (3).
In contrast to other risk factors for atherosclerosis, hyperhomocysteinemia is correctable with folic acid and/or vitamin B12 supplementation. In fact, the majority of patients with significant increase in homocysteine levels responded adequately to vitaminic supplementation.
As suggested by Wei and co-investigators highÂ¨Cdose corticosteroids seemed to be associated with a higher risk for cardiovascular disease. Our data suggests that corticosteroid therapy induced a significant, and to some extend dose-related, increase in homocysteine levels, and suggests a new atherogenic and treatable mechanism of corticosteroids.
References 1.- Wei L, MacDonald TM, Walker BR. Taking glucocorticoids by prescription is associated with subsequent cardiovascular disease. Ann Intern Med 2004; 141: 764-770. 2.- Souverain PC, Berard A, van Staa TP, Cooper C, Leufkens HGM, Walker BR. Use of oral glucocorticoids and risk of cardiovascular and cerebrovascular disease in a population-based case-control study. Heart 2004; 90: 859-65. 3.- Martinez-Taboada VM, Bartoloma MJ, Fernandez-Gonzalez MD, Blanco, R, Rodriguez-Valverde V, Lopez-Hoyos M. Homocysteine levels in polymyalgia rheumatica and giant cell arteritis: influence of corticosteroid therapy. Rheumatology 2003; 42: 1055-61. 4.- Duhaut P, Pinede L, Demolonbe-Rague S et al. Giant cell arteritis and cardiovascular risk factors. A multicenter, prospective case-control study. Arthritis Rheum 1998; 41: 1960-5.
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