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.

 

SfE BES – Call for abstracts!

The annual Society conference, SfE BES, takes place this year in Brighton on 7-9 November 2016. It’s a great chance to network with colleagues, showcase your work and explore new research in your area of endocrinology. Our programme of events is varied yet specific – bringing together the best of basic science, clinical investigation and clinical practice, you have the chance to expand your horizons into other parts of the field whilst also attending those lectures which are really specific to you.

The submission system for abstracts is open until midnight on Wednesday 22nd June – so you have more than enough time to polish your final abstract and send it along. It’s not just a chance to show your colleagues across the whole field of endocrinology what you’ve been working on – it’s a chance to tell them why what you’ve been working on is important.

Last year at SfE BES, a great programme highlight was a session entitled ‘Evolving model systems for complex tissues’, which was chaired by Kevin Doherty and Shareen Forbes. In the ’90s, manipulation of human embryonic stem cells (hESCs) was something of a new thing. It was anticipated that the ability to grow human tissues in culture using hESCs would provide incredible model systems for drug development, toxicity testing and cell therapy.

However, it wasn’t until 2005 that reliable markers had been developed and a significant number of important signalling pathways had been elucidated in the path to differentiation. By this point, some ten years later, finally a tool box existed for nearly every tissue type. This lead to some of the first clinical trials, using pluripotent cells to treat age-related macular degeneration. However, liver disease, diabetes and neurodegeneration were still elusive and challenging goals.

By 2014, fully functional human beta cells has been generated, and they took only 45 days and 7 stages in culture. This was a hugely exciting moment for diabetologists and researchers across the world. But then, of course, the question sprang up: could they be used as a source of islet cells for replantation? Or would they merely serve as an invaluable model?

At Kevin and Shareen’s BES session, they gave a detailed overview of both the background to the field of complex tissue model systems, and the current state of basic science and clinical research, highlighting very recent advances, and discussing the potential future.

The stem cell field continues to expand rapidly. 2016 has already been the year that Chinese scientists grew functioning mouse spermatozoa from skin cells – these went on to fertilise egg which developed into embryos and grew to successful progeny. What will the second half of 2016 bring?

With over 1000 delegates, 100 abstract lectures, 10 plenary lectures, and an evening of awards and prizes, SfE BES is the best place for you to spread the word on your research, and meet the colleagues that you want to work with in future. Your lecture might be the one were talking about all the way into June 2017.

So submit your abstract now through our submission system. Submissions close on Wednesday 22nd June at midnight.brighton 2

See you in November!

World Health Day: Beat Diabetes

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There are currently 422 million people in the world who have diabetes. This figure is expected to double in the next 20 years. In light of this alarming trend, the World Health Organization is dedicating 2016 World Health Day: Beat Diabetes to raising awareness of this life-threatening condition.

For World Health Day we decided to raise awareness by asking two prominent diabetes experts about their work and the hurdles that they feel need to be overcome to beat this disease.

 

Dr Sof AndrikopoulosSof

Dr Sof Andrikopoulos is President of the Australian Diabetes Society and a Senior Research Fellow at the University of Melbourne. He is also Editor-in-Chief of two of our journals: Journal of Endocrinology and Journal of Molecular Endocrinology.

What is the focus of your current research?

My research strives to understand the genetic and biochemical mechanism(s) associated with beta cell dysfunction in type 2 diabetes. We recently identified a novel genetic cause for this dysfunction in a preclinical model (Andrikopoulos et al. J. Endocrinol 228:61-73, 2016).

How does your research have the potential to translate to a clinical setting?

While there has been a significant increase in drugs available to treat type 2 diabetes, none currently target beta cell dysfunction – the underlying cause of the disease. My group aims to address this.

Do you think the day will arrive when we’ll have beaten diabetes?

I truly believe that we will reach a point where we are able to effectively manage diabetes and avoid the associated life-threatening complications. This will be achieved by research focussed on understanding the genetic cause(s) of the disease.

What is the greatest highlight of your career so far?

My greatest achievement by far is to have mentored a number of scientists who are now forging their own independent careers in medical research.  Mentoring is the most important activity I engage in and I am extremely proud of all the scientists I have worked with.

 

Professor Nick Finer

Nick FinerAs a Consultant Endocrinologist at University College Hospital in London, Professor Nick Finer treats patients affected by diabetes and its complications. Here, Nick describes the progress that has been made during his career and his thoughts on the future of diabetes.

What have been the biggest advances in the field of diabetes in the last 20 years? 

Technologies such as glucometers, together with pen devices for insulin delivery, have allowed people with diabetes to achieve ever better glycaemic control. Cardiovascular risk management via statins has also had a huge impact on health improvement.

What are the biggest challenges you face in the treatment of diabetes?

Encouraging patients to understand that diabetes is never ‘mild’ and thus motivating them to reduce their personal health risks.

What do you feel needs to happen to enable us to beat diabetes?

We have to tackle the still growing devastation from ever-increasing obesity prevalence. Governments, societies and individuals have to reverse the unbridled proliferation of cheap, unhealthy food.

What is the greatest highlight of your career so far?

Seeing and being at the forefront of the transition of obesity from a curiosity to a cutting-edge scientific and clinical discipline.
To find out more about diabetes, visit You & Your Hormones, the official public information website of the Society for Endocrinology.

Patient Support Grant: How-To-Inject for adrenal crisis prevention

Every year, an average of around 30 people in England and Wales die from adrenal crisis, undertreated or undiagnosed Addison’s Disease*.

 Because of this the Addison’s Disease Self Help Group (ADSHG) teamed up with the Society for Endocrinology, which provided the kick-start funding for a how-to guide on giving an emergency hydrocortisone self-injection – an injection which could have saved some of those lives.

The aim was simple: to produce a series of short video clips which would give people with Addison’s – as well as their friends, family, school or work first-aiders – the knowledge and confidence to administer the injection correctly, using any of the available drug formulations. The charity was fortunate to have the close support and involvement of one of the UK’s leading adrenal specialists, Professor John Wass, who explains when it is necessary to give an emergency injection. You can find all videos on the ADSHG website. Below, watch when to give an emergency injection.

Above video: Adrenal crisis: when to give an emergency injection from Addisons Disease Self-Help Group video hub. Interview with Professor John Wass, Addison’s Clinical Advisory Panel Chair.

We hope that this education tool will not only save lives and reduce the length of hospital stays, but improve the confidence of those with Addison’s, helping them to maintain independence and overall quality of life. It pays to be prepared!

Patient Support Grant

Thanks to the Society for Endocrinology Patient Support Grant, funding was provided to begin the production of these life-saving videos. These grants assist small charities and patient support groups who work with endocrine-related conditions, and aim to fund projects directly benefitting patients.

The deadline for 2016 grant applications is now closed, but you can read more about the grant here, and start planning your application for 2017! We would love to hear from you in our quest to support patients.

Learn More

Watch all of the videos on the ADSHG website: How-To Guide: Addison’s Disease. They are also signposted on the ADSHG Facebook Page and Twitter feed.

*To learn more about Addison’s Disease, visit the Society website, You and Your Hormones.