Expert Interview: Dr Shareen Forbes and Dr Richard Oram Discuss the Latest from ADA and the Impact on Diabetes Care in the UK

Dr Shareen Forbes, MBChB PhD FRCPE; Dr Richard Oram, PhD, BMBCh, BA(hons), MRCP


June 27, 2018

Dr Shareen Forbes: Welcome to Medscape UK. It's a great pleasure to be here at the American Diabetes Association meeting in Florida and with my colleague Dr Richard Oram, who's a clinician scientist from Exeter [University of Exeter Medical School], my name is Shareen Forbes and I'm a clinician scientist with the islet transplant programme in Edinburgh, Scotland [University of Edinburgh]. So Richard, we've just come out of a session to do with clinical trials in type 1 diabetes. What were the main highlights for you?

Dr Richard Oram: So we’ve both just come out of this session here, it was actually really full of energy. It was a really enjoyable session to be part of and for me the main reason for that was the clinical trial presented by Mike Haller from the University of Florida.

He performed the trial [TrialNet ATG-GCSF New Onset Study] using antithymocyte globulin (ATG) in people with new onset type 1 diabetes, and he had three arms in his trial - an ATG alone arm, an ATG with an additional drug called G-CSF [granulocyte-colony stimulating factor], which stimulates the bone marrow to make more white blood cells essentially, and then a placebo arm.

And he previously, in animal models and early human studies, has shown that there may be benefit in preserving beta cell function. But this trial clearly showed in their primary one year outcome that ATG alone provides benefit and C-peptide preservation. So this is a positive result and was received with great excitement, and it was really enjoyable to see the reaction of the audience and to hear the details of the trial.

Despite this being essentially a positive trial. It still leaves us with a few questions that came up during the session because ATG is a drug that, as you know from transplantation, can have some side effects including a, if you like, a mild, slightly allergic reaction at the time the infusion is given. So one of the discussion points in the session was the risk-benefit analysis. I think this is really relevant to UK physicians looking after people with type 1 diabetes, because as we've watched the field of immunosuppression treatments over the years, the key question that clinicians ask themselves is, with the improvements in technology, do I really want to advocate for treatments that may have significant side effects on the immune system on the patient, when I don't know the potential benefits? And if you like, that's still an unanswered question and something that people still need to think about going forward.

So will this trial change what we do in type 1 diabetes in the UK in the near future? Well no, but the reality is it does bring us one step closer to intervening in type one diabetes and it was received with great excitement.

Dr Forbes: And we'll watch to see what happens in the next year with the follow up extra year of data.

Dr Oram: Exactly. So the session we were in also had several other good talks. One was from the head of the NIH funded TEDDY study [Jeffrey Krischer, PhD, The Environmental Determinants of Diabetes in the Young] who also is a member of the TrialNet, the US organisation TrialNet who run clinical trials and he highlighted some really key points that may be alternative methods for trial design are needed in type 1 diabetes, and that we don't understand the basics of the biology of type 1 diabetes yet, and we may need to understand more about those basics before we can really crack immune intervention in type 1 diabetes.

So that leads us on to your session, because I think yesterday Shareen, you were talking about the UK experience of islet transplantation [The UK Islet Transplant Consortium—Utilizing Centralized Islet Isolation and Expanded Donor Criteria] which is in many ways linked to immune intervention in type 1 diabetes. So what were you talking about?

Dr Forbes: So first off the islet transplantation is indicated for people with type 1 diabetes in the UK who have severe problems with hypoglycaemia, recurrent hypoglycaemia, with impaired awareness of hypoglycaemia, who optimised medical therapy has not worked for them. So we were really talking about the UK Islet Transplant Consortium's experience. And this is the seven centres in the UK, that's Newcastle, Edinburgh, Oxford, two centres in London, Manchester, Bristol, and we've put together all the data. And I think one of the things that's really come out is that we use what's called an expanded donor criteria really to try and perform islet transplantations at a level that is meaningful in the UK to try and help these people. So we have donors who, that have donated their organs after what's called circulatory death. And that's quite unusual here in the US to utilise these sorts of organ donors. But we do it, and we do it successfully. We've had good outcomes. About 10% of the islet transplants in the UK are done with these donors. We also have donors who have high body mass indices and who are aged over 50. And again, this all comes under the umbrella of expanded donor criteria. And what we have shown in the UK is that, in fact, hypoglycaemia is eliminated, glycaemic control is improved and patients report awareness of their hypoglycaemia if that is still ongoing.

So I think that was exciting to see that we are performing about 30 transplants a year, and at this sustained level within the NHS. And that contrasts quite a lot with what's happening in the US where there are issues and there are problems with funding these sorts of procedures.

So, as I said, it was good to see that level of activity. But there was a lot of other things in the sessions. There was exciting information with regards to how islet transplantation may actually improve microvascular disease. So there was evidence, more evidence accumulating that retinopathy improves, as does neuropathy. And although we haven't got hard endpoints with macrovascular disease, there have been talks where they've shown that carotid intimal thickness actually regresses with islet transplantation and that's a surrogate marker. More is to be done, but I think that's a good starting point.

Dr Oram: That's really encouraging. Because I think, you know, I remember seeing quite small studies early on, but not knowing whether they would actually continue to show benefit. One of the things I was, as you were speaking, I was wondering was, do you think we've got it right in the UK with the numbers of people being referred? Do you think the right people have been transplanted? Or do you think there are more people who could benefit if the message was spreading the widely?

Dr Forbes: I think that's a good question. I mean, I think that we're only just seeing the tip of the iceberg. And we actually see people very late in the progression of their type 1 diabetes with a lot of medical problems, often with problems with their kidney function. And actually, perhaps if we saw these people earlier, if they had hypoglycaemia, which is likely, that they had severe hypoglycaemia and impaired awareness, earlier they may actually be able to undertake this sort of procedure better. But in the transplant centres, we have started now programmes, including the simultaneous islet kidney transplant programme. So that means that if people are referred and they have kidney failure, they can have an islet transplant as well as a kidney transplant, and this might be appropriate in somebody who has a lot of atheroma in whom simultaneous pancreas kidney transplant just isn't possible.

Dr Oram: So just as an outsider to this in a way. So if I had a patient who's really, really struggling with severe hypoglycaemia, multiple hospital admissions, life-threatening episodes, how would I find out who to refer them to if I was a regional endocrinologist?

Dr Forbes: Certainly it's on the website at Diabetes UK and all the principal investigators and clinical leads are actually on that and so the information is on the internet, so hopefully people can find that quite easily.

Dr Oram: OK, great. And I had one other question if that's okay. So the one of the other really interesting areas in type 1 diabetes at the moment is the rapid improvements in technology. And the idea that we made get better and better blood sugar control with ever, cleverer pumps, sensors and closed loop systems. Do you have a protocol that you have patients go through to have tried all those technology methods before they are transplanted?

Dr Forbes: I think that technology is right for the right person. I think that that we have had people in whom that's been the right thing to do, and they've gone through and utilised that technology to good effect and actually they haven't required the islet transplant. But there is a cohort of patients who, in whom, they find the technology too difficult to use. And that might be as a consequence of recurrent hypoglycaemia affecting their brain. And you know, them having actually very different, finding these sorts of technologies, very difficult to utilise. And in those patients, it's just not appropriate to go down that line. Having said all that, I don't think there's a problem with utilising that approach in terms of the people in whom technology works, go on it, see how they do.

It may not eliminate their, it may actually not improve their awareness of hypoglycaemia, and they may then go on to be referred for an islet transplantation, but use the technology side by side. So I don't think they should be viewed as mutually exclusive. I think I think we should be integrating it into our care plan.

Richard, yesterday you were giving a talk at a session with regards to the genetic risk score [Applications of the Type 1 Diabetes Risk Score]. And can you expand on the genetic risk score?

Dr Oram: I had a talk in a genetic session which covered several new areas in the study of the genetics of type 1 and type 2 diabetes.

So the talk I gave was trying to tell the story of how we started measuring the genetics of type 1 diabetes, not in the relatively complicated nomenclature of HLA typing, but turning that into a continuous variable. And using all the genetic information from genome wide association studies added together into a simple number - the genetic risk score. And this has benefits that it's a bit easier to understand, and it uses all the information genetics continuously so we get the maximum information from the genes.  And we've used that to answer a variety of different questions. The first one we started with was: could we tell the difference between type 1 and type 2 diabetes with a patient in front of us using a genetic risk score a diagnostic test? And in our first study, to our surprise, the answer was yes. And really quite well.

And what we actually showed in this study was that if we took people who were in the overlap between type 1 and type 2 diabetes where we weren't sure what the diagnosis was, a combined assessment of genetics, autoantibodies and clinical features was actually the best way to make a clinical diagnosis, and what it's likely to be the future of making the right diagnosis in type 1 diabetes by combining all these features together in simple prediction models. We've already worked on a kind of beta version of an app that doctors could use to integrate this information.

We've built on some of the genetic risk score work to answer key questions in large datasets, such as UK Biobank, a phenomenal study of 500,000 people, where we have all of their genetic data as well as hospital episodes, detailed questionnaire data and baseline measurements. It's absolutely staggering as a study in revolutionising the field of genetics and medical research, simply by the scale of this study.

We used UK Biobank actually to show that type 1 diabetes is far more common in older life. It's always been assumed to be a disease of childhood and is reported that way in the textbooks. But the reality is you probably know from first-hand experience in the clinic is there are definitely people with type 1 diabetes presenting in older age. And commonly they’re misdiagnosed. And we showed this in a UK Biobank study where over 40% of people with type 1 diabetes defined by our genetic risk score presented over the age of, over the age of 30.

Finally, one of the most fun studies for me to have be in is to use genetic risk to predict future type 1 diabetes. And I've worked with two different US funded trials, organisations, TrialNet, and the TEDDY study, to show that you could predict future onset of type 1 diabetes using the genetic risk score. The exciting thing for me has been that collaborators in Germany -  Anette Ziegler and Ezio Bonifacio - have now got large scale funding from the Helmsley Foundation, over $50 million to screen hundreds of thousands of babies in Germany to identify those at highest risk, for low-risk intervention studies using simple oral therapies to try and prevent type 1 diabetes. To me that almost feels like science fiction, but it's really great fun to be involved with.

Dr Forbes: So can I ask you though, you know in the US, we’re in the US, there’s a very multicultural society, large prevalence of Hispanics, do you think your genetic risk score can traverse the waters and actually be applied to multiple ethnic groups?

Dr Oram: So that's a really good question. And almost every genetic study you ever look at you have to think in your mind, does this just apply to this population? Or does it apply to people of other ethnicities? And that's a key question we didn't answer with the first paper but we're now invested in looking at other cohorts. So within the UK we have people with diabetes of different ethnicities in UK Biobank, and then we have collaborators in India to assess the use of the genetic risk score in East Asians, sorry not East Asians, South Asians with type 1 diabetes. Our initial pilot work suggests it’s still very strong. We've ended up collaborating with several US studies to ask the same question in ethnicities common in the US like African-Americans. 

So, the first example of this is really work with the SEARCH for Diabetes in Youth study, or the SEARCH study, which is a US-wide study of paediatric diabetes. They have a large cohort of African-American children with diabetes. And our initial data is still under analysis, but the results, let me say, look positive.

The University of Florida have looked at Hispanics and the early data in Hispanics looks actually equally strong as white Caucasians, possibly even stronger. And I collaborated with Dan Perry [Daniel Perry, PhD] last year, and we just published [Application of a Genetic Risk Score to Racially Diverse Type 1 Diabetes Populations Demonstrates the Need for Diversity in Risk-Modeling] the fact that it likely works in Hispanics. That was out earlier this year.

Dr Forbes: Excellent. Well, thank you. That's just some of the highlights from the American Diabetes Association. Thank you for watching.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: