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Editorials

Glucocorticoid replacement

BMJ 2014; 349 doi: https://doi.org/10.1136/bmj.g4843 (Published 30 July 2014) Cite this as: BMJ 2014;349:g4843

Re: Glucocorticoid replacement

BMJ Rapid Response
Anjali Amin, clinical research fellow, Amir H Sam, senior lecturer in endocrinology, Karim Meeran, professor of endocrinology

Ragnarsson and Nilsson state that glucocorticoid replacement should be as similar to normal endogenous cortisol production as possible. At present no oral glucocorticoid, including oral hydrocortisone, is able to accurately replicate the normal circadian rhythm of cortisol. There is an urgent need for randomized trials comparing hydrocortisone with small comparable replacement doses of prednisolone, as at present hydrocortisone is being prescribed by the majority of clinicians without a sufficient evidence base. Comparison of different glucocorticoid potencies is difficult as lower doses may result in patient fatigue, but clearly will result in fewer side effects. Also reproducing the effect of a continuous synthesis of cortisol by the adrenal can only really be attained by the use of cortisol infusion pumps. When given intravenously, hydrocortisone has a half-life of 100 minutes whereas oral pharmacokinetics are completely different (1).

Assuming that patients prefer a once daily dosing, prednisolone happens to have a half-life that will enable this. The difference in potencies and half-lives of the various glucocorticoids make them very difficult to compare. The standard replacement dose of hydrocortisone in the 1990s was generally 30mg (20mg in the morning and 10mg in the afternoon), but the average patient in 2014 receives a total daily dose of between 15mg and 20mg. What is the correct true replacement dose?

When deflazacort became available as an alternative steroid about 20 years ago, the manufacturer (Shire) claimed that the drug had a lower incidence of steroid-induced unwanted effects compared with prednisolone. However, this claim was later withdrawn at the request of the Medicines Control Agency following its review of the cited data (2). The lower prevalence of side effects was proven to be purely due to the fact that deflazacort was less potent than prednisolone (3).

Ragnarsson and Nilsson are attempting to mount a similar scare campaign and state that patients treated with prednisolone have adverse cardiovascular risk. However the paper they have quoted (4) includes patients on dexamethasone in the prednisolone group. The data on the effect of prednisolone on bone mineral density remain inconclusive (5, 6).

Their statement that doses of standard hydrocortisone and Plenadren in the only known trial were comparable is simply not true. Systemic absorption of Plenadren is lower than that of standard hydrocortisone (7) and the Summary of Product Characteristics issued by the European Medicines Agency clearly states that Plenadren has a lower bioavailability than standard hydrocortisone (8) and hence doses in the trial are not comparable. A study comparing Plenadren with a 20% lower dose of hydrocortisone is required to determine any true metabolic effects.

Quality of life data showed negligible differences between Plenadren and conventional hydrocortisone in an open-label study, and although it was shown that patients prefer a once daily formulation to multiple daily doses, compliance was no different between the two formulations. (7). The adverse event data showed that fatigue was more common in patients on Plenadren, perhaps suggestive of under-treatment.

The randomised controlled trial of hydrocortisone 10+5, hydrocortisone 10+5+5 and prednisolone 5mg referred to by Ragnarsson and Nilsson (9), in fact showed that hydrocortisone 10+5 had an SF 36 physical function of 43.9±10.5, which was significantly higher than hydrocortisone 10+5+5 (physical SF36=40.7±13.4) but not prednisolone 5mg (physical SF36=42.8±12.2). If anything, this paper suggests that prednisolone 5mg has a similar SF36 to the lower dose of hydrocortisone, although there was in fact no significant difference between prednisolone and either dose of hydrocortisone. Furthermore, the difference in SF-36 of about 3 points, although statistically significant, is likely to be too small to be clinically significant. The smallest clinically important difference is 10 for most chronic conditions (10).

As a result of widespread interest following publication of our editorial (11), we have developed a mass spectrometry assay for the measurement of prednisolone, thus allowing measurement of glucocorticoid exposure, dose-titration and avoidance of over-treatment. The reported plasma half-life of prednisolone is 130-250 minutes, although the biological effect of prednisolone is longer (12, 13). In our assay, we found the plasma half-life of prednisolone to be 168-204 minutes, thus comparable to published data. The only way to determine the differences between the benefits and risks of any steroid is to find the correct replacement dose and then undertake a randomized controlled trial of prednisolone replacement and hydrocortisone replacement.

In the current vacuum of evidence (14), we need a study with hard endpoints on glucocorticoid exposure, such as glucose handling and bone markers as well as more difficult to measure markers such as SF36. We are planning to undertake such a study.

References

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8. European Medicines Agency. Annex 1 Summary of Product Characteristics. 2013.
9. Benson S, Neumann P, Unger N, Schedlowski M, Mann K, Elsenbruch S, et al. Effects of standard glucocorticoid replacement therapies on subjective well-being: a randomized, double-blind, crossover study in patients with secondary adrenal insufficiency. Eur J Endocrinol. [Randomized Controlled Trial]. 2012 Nov;167(5):679-85.
10. Wyrwich KW, Tierney WM, Babu AN, Kroenke K, Wolinsky FD. A comparison of clinically important differences in health-related quality of life for patients with chronic lung disease, asthma, or heart disease. Health Serv Res. [Comparative Study
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11. Amin A, Sam AH, Meeran K. Glucocorticoid replacement. Bmj. [Editorial]. 2014;349:g4843.
12. Pickup ME. Clinical pharmacokinetics of prednisone and prednisolone. Clin Pharmacokinet. [Review]. 1979 Mar-Apr;4(2):111-28.
13. Al-Habet S, Rogers HJ. Pharmacokinetics of intravenous and oral prednisolone. Br J Clin Pharmacol. [Clinical Trial
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14. Pearce SH. Insufficient evidence to favour prednisolone over hydrocortisone in glucocorticoid replacement. Bmj. [Letter]. 2014;349:g5510.

Competing interests: No competing interests

30 September 2014
Karim Meeran
Professor of Endocrinology
Anjali Amin and Amir H Sam
Imperial Centre for Endocrinology
Charing Cross Hospital