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
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
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
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.
The Endocrine Post 
Apologies for a non-medic commenting on a taster article in your excellent magazine. As a patient I would much prefer to stick with hydrocortisone until such time as clinical trials demonstrate that there is a better alternative. for me, the convenience of once per day administration and cost saving don’t equate to an ethically sustainable solution. My survival and Qol are of paramount importance. I am not merely a statistic.
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Safety is indeed paramount. Prednisolone is longer lasting than hydrocortisone and thus safer. No patient should die of an Addisonian crisis, but it still happens. A prismatic case was presented by Bruno Allolio (http://www.eje-online.org/content/172/3/R115.full), in a patient on hydrocortisone who developed probable norovirus. The treatment should have been earlier parenteral hydrocortisone, but the patient was on oral hydrocortisone. Further oral hydrocortisone was probably not absorbed. Prednisolone would be no better once the vomiting has started, but any previous prednisolone binds more avidly to the receptors, and has a longer half life, so might have bought the little bit more time that he needed once he got to hospital.
If I had developed an analogue of hydrocortisone with a double bond making the new steroid that we call prednisolone, but gave it a new name, and launched it as a once daily drug, I could market it for a large amount of money. The fact that it already exists for other uses, making it very cheap (luckily) does not make it an inferior drug. I agree that we need a large randomised controlled trial to compare prednisolone with hydrocortisone, but because prednisolone is so cheap, no one is interested in funding a trial, because there is no money to be made. Other longer lasting versions of hydrocortisone might be studied, because the money that could be made from them is so vast. Thus the cost agenda is skewing the research that is possible. We cannot study cheap medicines easily.
Prednisolone 3 – 5 mg once daily is used as first line replacement in some countries, and I have spoken to clinicians around the world who have always used it. In primary adrenal failure, the need an extra 50 mcg of fludrocortisone quite often when switching from hydrocortisone to prednisolone, but the challenge is to get the dose right.
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My husband would testify to the fact that I am not a ‘cheap’ woman, and yet I am perfectly content taking prednisolone, saving the NHS much needed cash! Professor Lightman argues that prednisolone is unphysiological………..but, so am I! I am awoken rudely early in the morning by my commuter boys and so my long day begins – I work hard and play hard and am grateful that I have a medication that can keep up with me. Things weren’t hugely different on hydrocortisone which I took for about 10 years, but you get to feel like one of Pavlov’s dogs – drawing attention to yourself whenever the phone alarm goes off to remind you to take your pills. Compliance has not been my problem with either medication, not just due to Pavlov programming, but because I know that my existence depends upon my pill popping (MEN2a steroid-dependent after bilateral adrenalectomies). I have educated myself about regular and emergency cortisol replacement and therefore have a considerable degree of confidence when dealing with my medication – I have experimented with my prednisolone dose myself (got to keep you consultants on your toes you know) and am currently happy on an ordinary day with a 3+2mg dose. I increase this according to what I am expecting to be doing during any day, and upon how I feel generally, so it’s pretty fluid at times. Although I am still prone to skin colour change despite keeping out of the sun as much as possible, this was actually particularly more marked when I was taking hydrocortisone (17.5mg) – I dearly wished I had been on that fabulous holiday that everyone remarked I must have been on to get such a great suntan! I was pleased to be able to donate blood to help develop the new assay (an important step) and would be only too pleased to be involved in research/trials on this topic as I believe that prednisolone is a totally viable option for many patients. We need to educate patients and give them confidence about trying different meds and doses, but most of all, we need to get down to doing a clinical trial!
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Why did you switch to prednisolone?
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Hi I am a practicing endocrinologist for more than 25 years with special interest in hypothalmo-pituitary and adrenal disorders working in Singapore. I worked in one of the hospitals where hydrocortisone was not easily available initially. I therefore used cortisone acetate, and subsequently used either prednisolone or hydrocortisone (which was introduced later).
I have a number of patients on my follow up who are maintained over the years on prednisolone therapy. Some of my patients never wanted to switch to hydrocortisone despite my persuasive attempts, as they had felt well on maintenance prednisolone. My learning as well as guidance and therefore my practice prompted me to introduce a twice daily regime (dosing 5 mg in the morning and 2.5 mg in the early evening). Some of my patients have, over the years, felt that the evening dose was not necessary. They took it upon themselves to stop the evening dose (against my advice). They have remained well over the years – It has always been a mystery to me why they never had “Addisonian” crisis, or got into symptomatic hypocortisolaemic states. I can recall one lady who developed lymphocytic hypophysitis (with severe documented hypocortisolaemia) maintained herself well on just 3 mg of prednisolone (she tailed it down against medical advice but she would not budge) and never to date had any adrenal crisis states..
I do have another group of patients who recover after successful surgery from Cushing’s and I often use prednisolone more for this group because of the availability of 1 mg tablets of prednisolone which gives me greater flexibility in tailing down doses. Again, I often started off with a twice daily dosing. In tailing down the dose of prednisolone my experience has been that once they reach the 5 mg prednisolone threshold – a single daily dose is enough for them. I do have two patients who have cured Cushing’s and who need lifelong steroids (documented steroid deficiency) and are maintained well on 5 mg prednisolone daily. I have never attempted trying lower doses.
At long last, I am delighted to know of Professor Karim Meeran and his colleagues’ studies which has resolved one mystery in my practice of clinical endocrinology – where the patient has taught me more than what the original studies would seem to have suggested. Again, an illustration of how our patients teach us more than what we commonly assume.
Certainly it appears this is an area worth doing further studies .
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I read the editorial by A. Amin and yourself in BMJ 2014. In the German Endocrine society (Deutsche Gesellschaft für
Endokrinologie) there is a Plenadren (R) hype, driven by the marketing interests of ViroPharma and the author (s) of most plenadren papers (G. Johannssen et al.), who are shareholders of that company. I agree with the statement in your paper that the pharmacokonetics of prenisolone could be ideal for substituting patients with adrenocortical insufficiency (one dose in the morning). Working at the university hospital of Freie Universität West- Berlin I saw, before the fall of the iron curtain, several patients from Jugoslavia or other eastern European countries with prim. or sec. adrenal insufficiency, who had to be placed on prednisolone (P) because no hydrocortisone (HC) was available in those countries. Our colleagues in East-Berlin told me later that this was also the case in East-Germany.
After becoming an emeritus in 2001, I worked partime in a large endocrine practice in Berlin treating many patients with adrenal insufficency. I wrote a review on this disease in New Engl. J Med. 20 years ago (1996, 335, 1206-12) and published some papers especially on mineralocorticoid substitution with 9 alpha flurcortisol. I have never prescribed Plenadren. In patients, who have difficultuies taking two or three daily doses of HC, I recommend to try 5 or 4 or 3 mg of Prednisolone early in the morning, usually starting with 5 mg and then slowly reducing the dose to the smallest one on which the patients feel well (In Germany we can prescribe 1 mg, 2 mg and 5 mg tablets). Alleged detrimental metabolic or psychic effects of Prednisolone as mentioned in the letter of P. C. Hindmarsh in his letter in response to your article (BMJ 2014, 349, g5518) seem to be nonsense if equivalent dosages are administered. East – German patients were usually substituted with between 5 and 7.5 mg P per day, which was too high a dose for many patients and may lead to osteoporosis and other longtime metabolic sequelae.
In the first Johannssen paper of 2012 on plenadren, 30 mg HC were given to the control group of Addsonians, which dose is also too high. I regard the relatve GC strengths of 1 : 6 between P and HC as most likely. Most of my patients taking 3 to 5 mg p in the morning (after finding the best dose, see above) stick to that regimen. Perhaps every fifth patient switches back to HC twice daily. With P you often need 0.05 mg more of fludrocortisol than with HC also a GC. Do you have experience with Prednisolone for substitution ? What is the opinion of British colleagues, and is Prednisolone (for substitution) recommended in guidelines of The NHS ?
I am now 80 years of age and have stopped practicing, but I am still a consultant (for special cases) in my former group practice. I would like to share youre experience. It would be wonderful if some colleagues would start a comparative study between Plenadren and Prednisolone in prim. and sec. AI. Of Course, Viropharma is not interested in such an enterprise.
Another interesting study would be a comparison between Chronocort (R) (retarded P) late in the evening (1 dose) and HC twice a day, because all regimens discussed so far (HC, P and Plenadren) do not mimic the early morning surge of plasma cortisol around 4 a.m in healthy subjects.
On the other hand, the steroid plasma concentration fetishism (e.g. in the Hindmarsh letter) is short-sighted, since the molecular effects of GCs (transactivation or-supperssion, transcription into protein products and the half life of those proteins) last much longer than the presence of the steroids in plasma.
Wolfgang Oelkers
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As a patient taking 10-5-5mg of HC daily, this is a topic that greatly interests me. I do very much like the idea of only having to take a once-daily morning dose of medication, but like the other patients I do also want to see some kind of data that confirms that there would be long term effects of Prednisolone on my bones. I feel safer taking HC as I know it only has a 5-6 hour half life. Seeing the ‘case history’ above showing patients manage very well on a dose of Prednisolone is encouraging. Also the cost of HC in the UK is undoubtedly ridiculous, but I agree with Trudi in the first reply, cost alone is not going to be enough to persuade me…..
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I have secondary adrenal insufficiency and was very ill on HC no matter what doses were tried. I am now on prednisolone (18 months), and finally my AI is under control and am keeping away from ER, where I used to end up constantly on HC. However, I have to split my 7.5mg dose into three. 3 3/4am, 2 1/2mg at 2pm and 1 1/4mg at bedtime. It took keeping a diary over those 18 months to get to the perfect dose and timings. Amazingly I sleep since starting the bedtime dose and wake up without that running on empty feeling. I am so much stronger on prednisolone compared to HC which seemed to run out after 2 hours. They say you need hc for updosing if unwell because pred is too slow, but I can turn things around in 20 minutes.
My only concern is when I relocate to Mexico next year as no prednisolone only prednisone available. I know there isn’t a straight conversion and the thought of having to start over finding the correct dose is very worrying. Any thoughts on that?
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While you shifted from HC to P..what was the process. Did you stop HC on one day and started pred next day?
Secondly was single dose of P was not sufficient?
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Yes, I stopped hc and started pred next day. One dose of pred leaves you 12 hours without steroid coverage and was no good. Splitting the dose far better.
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Hi,
I am staff nurse doing a presentation about safe and efficacy of prednisolone as the first line of treatment for glucocorticoid supplementation in patients with AI.
I wanted to ask please where can I get the full story of the debate between the three professors please?
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In my opinion it’s an individual thing, there is no “one size fits all” answer. If you can afford Cortef/hydrocortisone then go for it. I’m going to switch to prednisolone due to cost. I’ve been taking 5-10 mg HC per day for a few years, with short tapers of prednisolone in between to help with pain, inflammation and allergies. I’ll be switching to 2.5 mg of prednisolone per day – and will most likely continue doing tapers here and there. The way I prefer to do that is starting at 30 mg prednisolone per day, and reducing the dose by 5 mg per day, 30-25-20-15-10-5 milligrams, days 1-6. Most doctors don’t know how to do this and will typically just put you on 20 mg for a week to ten days. Which is fine, but tapering is probably better. 2.5 mg prednisolone will be equivalent to abour 12.5 mg of HC. The actual half life of HC is just 1.5 hours, prednisolone is ~3 hours.
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So I have been desperately trying to research this. I was switched to HC when diagnosed SAI. I tried 10-10, then 10-5-5. On both regimes I gained weight, yet in the afternoon got low cortisol symptoms. I switched to pred, my local endo said daily was fine. However by 5pm I was nauseous, lightheaded and headache. I moved to centre of excellence who switched me to twice daily increasing from 5mg to 7.5mg of pred, split as 5/2.5. I have reduced that to 4.5,, split as 3/1.5. However I noted Prof Meeran stated those on lower doses but splitting the dose had a higher exposure. So I have switched to daily. I cope ok in the day, but wake feeling my tank is on empty. I note from his graphs though, that all patients were extremely low cortisol after 14 hours. So effectively leaving us for 10hrs with no cortisol. I would love to have it explained how daily dose can be justified if after 14hrs we are running on empty
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