Should prednisolone be the first line for glucocorticoid replacement in adrenal insufficiency?

At 18.30 on Monday 7 November Professor Jeremy Tomlinson is chairing a debate on the treatment of adrenal insufficiency at SfE BES 2016. Ahead of the debate, we asked Professors Stafford Lightman and Karim Meeran to give you a little taste of their stance on this hot topic in endocrinology.

 

Professor Jeremy Tomlinson, University of Oxford – Chair

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The optimal strategy for glucocorticoid replacement in patients with adrenal insufficiency remains a contentious issue. In the majority of cases, hydrocortisone is used, but there are issues relating to the need for three times a day administration alongside the high costs of treatment. Are there alternatives?

Prednisolone is significantly cheaper, has a longer duration of action and therefore can be administered twice daily. However, it is a synthetic glucocorticoid that does not act in an identical way to hydrocortisone.

Head-to-head comparisons with meaningful clinical end points are lacking, and in the modern NHS, treatment costs play an increasingly important role.

Let the debate begin!

 

Professor Stafford Lightman, University of Bristol – AGAINST

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The evolution of Homo sapiens from early mammals has taken about 200,000,000 years. During this time we have developed many highly specialised physiological systems –including the key homeostatic system we call the Hypothalamo-Pituitary-Adrenal axis. This system maintains key cognitive, metabolic and immunological systems in optimal state and is also a rapid response system to protect us against stress. The hormone that has evolved to do this is cortisol.

In the absence of endogenous cortisol no-one would disagree that the gold standard therapeutic hormone replacement should be the closest we can get to normal physiology, so if we have to go second-best and provide a different steroid or pattern of plasma steroids it is incumbent on us to prove that this alternative treatment is as good as the best possible therapy available with the native compound.

Prednisolone differs from cortisol in many ways. Not only does it have different characteristics of glucocorticoid mediated gene transcription with no simple dose response comparison to cortisol, but its plasma half-life and metabolism are also unphysiological.

During the debate, I shall demonstrate why these aspects of prednisolone replacement are potentially disadvantageous at cognitive, metabolic and immunological levels. I will explain why I feel it would be dangerous to submit patients to such long duration therapy unless appropriate long term studies are able to show non-inferiority of this regime.

 

Professor Karim Meeran, Imperial College London – For

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Patients with endocrine deficiency need replacement therapy.

We are getting better at making new analogues of replacement hormones that are more patient friendly and improve compliance by lasting longer. Thus for insulin, we have moved away from normal human insulin to analogues of insulin that have variable half-lives, but are a totally different molecule. There is no evidence that the new analogues are any better than native insulin, but production of some preparations of native human insulins have ceased and many of us use these new insulin analogues. Vasopressin is replaced with a modified molecule, 1-desamino-8-D-arginine vasopressin; the D-enantiomer is used (which never occurs in nature) because it lasts longer. The argument in some quarters that “natural” cortisol would be better thus has no basis.

Similarly, rather than give hydrocortisone several times a day, we need to modify the molecule slightly by inserting a double bond, which increases its half-life and potency, and enables once daily administration. A slow release preparation has been developed and costs £400 per month, but it is far better to use a drug that has an appropriate half-life.

We don’t need to develop one because, remarkably, prednisolone has a half-life that is perfect for a once-daily administration. It happens to be extremely cheap, but that should not deter us from using it!

We now have an assay available for prednisolone, and present data at a number of posters at the BES in November confirming that a once-daily dose of prednisolone 3mg is equivalent to hydrocortisone 10mg plus 5mg plus 5mg. I have converted several patients, who regularly report how well they feel on prednisolone 3mg, and how much easier it is to take.

The main reason that patients should take once-daily prednisolone is its convenience. Added benefits for those in the UK are the low price of prednisolone compared to hydrocortisone, which is substantially more expensive in the UK than in other countries because of a peculiar licensing issue, and the fact that the NHS is not allowed to import it.

We have a serious problem in the UK with the cost of hydrocortisone, and every patient who is switched to prednisolone will save over £100 per month.

 

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