Welcome to the Hot Topics podcast from NB Medical with Dr Neal Tucker. The highlight of this episode is our interview with Prof Miriam Santer, lead author of recent research in the BMJ exploring the effectiveness of spironolactone for acne in women.
Does it work? Is it a treatment for general practice? And if so, is it safe, what monitoring is required, and where does it fit with current acne pathways?
In the news, we think about the current issues around physician associates in general practice. In research we have two papers on diabetes: first, in the Lancet, is a new once-weekly insulin injection as effective as a daily treatment for type 1 diabetes; and second, in JAMA, is the additional tirzepatide better than prandial insulin in addition to glargine for managing type 2 diabetes?
References
Eczema Care Online
BMJ Spiro for acne
Lancet Once weekly insulin vs daily insulin in T1DM
JAMA Tirzepatide vs prandial insulin in T2DM
www.nbmedical.com/podcast
Welcome to the Hot Topics podcast from NB Medical with Dr Neal Tucker. The highlight of this episode is our interview with Prof Miriam Santer, lead author of recent research in the BMJ exploring the effectiveness of spironolactone for acne in women.
Does it work? Is it a treatment for general practice? And if so, is it safe, what monitoring is required, and where does it fit with current acne pathways?
In the news, we think about the current issues around physician associates in general practice. In research we have two papers on diabetes: first, in the Lancet, is a new once-weekly insulin injection as effective as a daily treatment for type 1 diabetes; and second, in JAMA, is the additional tirzepatide better than prandial insulin in addition to glargine for managing type 2 diabetes?
References
Eczema Care Online
BMJ Spiro for acne
Lancet Once weekly insulin vs daily insulin in T1DM
JAMA Tirzepatide vs prandial insulin in T2DM
www.nbmedical.com/podcast
It's Friday, the 10th of November, and this is the Hot Topics podcast. Welcome to the Hot Topics podcast from NB Medical. Neil Tucker here once again to see you through the next few minutes and as usual, we will be talking about the latest general practice news two new research papers this week, one's looking at type one diabetes and one's looking at type two diabetes. And then the highlight of today is the next in our series of interviews with the authors of practice changing research, and I was lucky enough to have a chat with Professor Miriam Santa, who has recently published in the BMJ on the roller spine Ron, a lactone for acne management in primary care. I mustn't forget to tell you what's going on with NB Medical over the next few weeks. So tomorrow morning that's tomorrow morning for me. I don't know when you're listening to this podcast, but that's Saturday, the 11th November we're doing a live abnormal blood results course next week. So Friday, the 17th, we're doing our Hot Topics and managing obesity and overweight course. The day after, on the 18th, we're doing our new urgent care course. Friday, the 24th, we've got our new to general practice course. That's great for ST3s, for first fives. Come and join us for that. The day after we're doing a live Hot Topics course. I'm one of the people running that, so come and join me for that. And then second December we've got our Hot Topics and Diabetes course. That's just been updated as well. It's all going on. Remember, if you sign up to NB Plus just over £30 per month then you can come on all of these courses live and on demand. Loads more as well included. That's a big shout out for NB On Call. So this is our new forum. It's integrated into the nbmedicalcom website in your dashboard. So if you want a place to discuss clinical or non-clinical topics in somewhere that's more secure than social media, then check out NB On Call Right.
Speaker 1:What's been going on in the news? Oh yes, it feels like general practice is going to war with itself. The BMA has called for an immediate pause to the recruitment of physician associates in general practice, citing concerns over the increasing trend of physician associates being used to substitute GPs. Perhaps this is all coming to a head right now after reports of GP locums struggling to find work and even having shifts cancelled, and that they're effectively being squeezed out by the ARRS roles. If you read the GP forums, you get a lot of very polarized responses here. I think this is a very complex issue, but it doesn't have to be that people sit on one side of the fence or the other.
Speaker 1:The reality is, for the last few years, general practices have been really struggling with workload, desperate for more bodies on the ground to help meet patient demand. Gps themselves have been unable to provide more, and so other patient facing clinical roles have emerged these paramedics, physios, pharmacists, and then, of course, we have physician associates. Now these other practice roles don't seem to be causing the same amount of ire. This might be because their roles can be perhaps better differentiated from a GP. For example, a pharmacist may be doing medication reviews, and that's quite straightforward for both practices and patients to understand. The physician associate, however, has been adopted into general practice in a role where there is significant crossover with what a GP might be doing. This coupled with a branding that makes them sound like a doctor, and then coupled with a practice's perhaps inability or maybe lack of desire to clearly differentiate them from a GP when a patient is booking an appointment, because, ultimately, reception just need to put a patient somewhere and they really don't want the patient going. Oh well, that's not a doctor, so I don't want to see them.
Speaker 1:All of this, I think, has contributed to the rising disquiet amongst GPs. But I think it's unfair to insinuate that physician associates are bad or dangerous. It is, of course, true that they have less clinical training than you would do as a GP, and also less than you would do, perhaps, as a nurse, as a paramedic, as a clinical pharmacist, who will have gone through several years of a degree and then likely had several years of clinical experience coming out the other side before going into general practice. But the bigger issue is how practices choose to use physician associates. If they're seeing undifferentiated patients, as a GP might do, then clearly that's not appropriate. About a year ago we had that BBC Panorama Expo Zay on some of those practices owned by operos which were being run or staffed almost exclusively by physician associates and then overseen by one GP between multiple practices. Clearly that's clinically inappropriate and also, I imagine, very stressful for those individuals. Ultimately, we need to be using different clinicians with different skill sets in different ways within practices.
Speaker 1:I think it's important that we make sure we don't demonise physician associates. I suspect that a lot of this for raw is not actually about physician associates at all, but about the increasing anger around the devaluing of doctors and especially GPs. Healthcare policy makers seem to fail to understand the importance of training and experience and of a specialist generalist. The RCGP this week has once again been pushing the idea about GPs being consultants in general practice and also rebranding GP trainees as GP registrars. Pretty sure they used to be GP registrars. Why do we ever let that go? But I think these are positive moves so that we can feel value in ourselves once again. When we do that, perhaps we'll be less concerned about what a physician associate is called.
Speaker 1:All of this argument in England of course has the overlay of the additional roles reimbursement scheme providing subsidised labour to practices. But let's not forget where this has come from. This has come from a place where there has been not enough GPs to meet patient demand and trying to find a way to fill the gaps. And I'm sure that for the vast majority of practices around England they're not replacing GPs with ARRS roles, they're just trying to make it through the day. There's still a list a mile long of GP vacancies on the LMC recruitment website. Things have changed rapidly in the GP workforce over the last few years. Inevitably it's going to take a bit of time to work this all out. Who's best doing what where. But while we're doing that, let's make sure we all stay friends.
Speaker 1:Crikey, when I started that I had absolutely no idea I would go on for so long. I think I almost owe you guys an apology. I was going to talk about anastrasol being in the news as a preventative agent against breast cancer for postmenopausal women and the terrible communication that NHS England had with general practice before they did their press release, but I'm sure you're already all aware of that and you can read about that in a Hot Topics blog on the MBmedicalcom website. Instead, let's get on with the research Now. While both of these papers are on diabetes one is on type one and one is on type two, and you might as well consider them as entirely separate conditions. The first paper was published in the Lancet last week and this one just blew my mind, because this is a phase three randomized trial looking at weekly insulin Once, weekly insulin.
Speaker 1:I think that's absolutely mind boggling. If you're a type one diabetic, you have a choice you either inject yourself with insulin or you die. So everyone goes with injections. But if there was an option to inject yourself less frequently, I'm sure most people would be really excited about that. There are other potential benefits, as the authors of the paper point out. So it's not infrequent that people will miss their basal insulin dose 22% of people are reported to miss at least one basal insulin dose in every 14 day period. This increases glycemic variability. They have less glycemic control, potentially exposing themselves to long term complications, but also to short term increased risks of diabetic ketoacidosis. A once weekly injection, therefore, could solve this problem and potentially be safer for the patient.
Speaker 1:Now this is a pharma sponsored study by Novo Nordisk, so they're actually comparing this new medication that they've produced, this once weekly insulin called Icodec, against one of their other products, a daily basal insulin called DeGlue Deck. Adults with type one diabetes and an HbA1c of under 86 or under 10% were randomized to have either weekly Icodec or once daily DeGlue Deck as part of their insulin regime, and they would still be having bolus doses of a rapid acting insulin two or more times a day, and then they were followed up for 52 weeks. The primary endpoint was changing HbA1c at 26 weeks. That was the main phase of the trial, and they followed them up for a further 26 weeks as part of a safety extension and they were looking for non inferiority of Icodec compared to DeGlue Deck, which was set at 0.3% in their HbA1c. Of 582 participants they found at 26 weeks HbA1c was 7.59% with Icodec and 7.63% with DeGlue Deck Remarkably close. This confirmed non inferiority of the weekly version and they were cheers all around Hooray.
Speaker 1:But wait before you get too excited. Things are a little bit more complex than that. As is often the way in life, as you're giving to one thing, you may be taking away from another, and so here we're trying to improve convenience but we're sacrificing flexibility. Once you've had that weekly injection, you can't really modify the effect that that is going to have on the body. And so, even with maybe adjustments to the bolus dose, they found that the overall rate of combined, clinically significant or severe hypoglycemic episodes increased.
Speaker 1:There are inton there are internationally set standards on acceptable levels of hypoglycemia with treatment, and the authors do point out that the time below 3.9 millimoles per liter blood glucose was well below those set targets of 4%. So to summarize, I guess we can say that this once weekly insulin certainly shows promise. It is efficacious, but there will be challenges, challenges around the risks that it may expose patients to of hypoglycemia. And, interestingly, whilst you and I may feel that this is one of those examples where more research is required, the final comment from the authors is further analysis of continuous glucose monitoring data and real world studies might provide additional insights on adjusting insulin dose to mitigate hypoglycemic risk. As part of the learning curve to explore the full potential of once weekly insulin ICOdec in type 1 diabetes, they seem to be suggesting that this data is strong enough to get the drug to market, that they're going to give it to patients and then, when things go wrong, decide how they could make it better. I'm not entirely sure that feels like the best way for patients to try and solve this problem.
Speaker 1:Let's move on to our second paper, and this is published in JAMA this week, and this is looking at patients with type 2 diabetes. The problem, of course, here is not a lack of insulin as in type 1 diabetes. It is insulin insensitivity, leading to hypoglycemia. Nevertheless, when we fail to get people's blood sugars well controlled, lots of patients with type 2 diabetes end up on insulin. Many experts and many clinicians feel that this is arguably the wrong treatment for this type of diabetes, and newer treatments such as GLP1 analogs would be a better option. Nevertheless, in nice guidelines it feels like GLP1 analogs have been somewhat demoted and unless you are very overweight it's hard to get access to those, whereas insulin is the treatment of choice. Really, when hypoglycemia has not been controlled through oral medication, then we get into the realms, the mystical realms for many of us, of which insulins to try. But generally speaking, a lot of this group would be on longer acting insulins and some of them will be on glar gene, a long acting, once daily insulin that all of the patients in this study were taking.
Speaker 1:The question here, then, was in patients who are already on oral therapy plus glar gene and still their sugars are high, is it better to add in to Zepetide, which has a dual mechanism by which it may reduce someone's blood sugars Firstly it's GLP1 agonist, but also it's a glucose dependent insulin atrophic polypeptide agonist as well or is it preferable to add in Prandial insulin so boluses around mealtimes? They recruited just over 1400 patients. Half of them had to Zepetide at various doses and the other half had three times daily insulin list pro with meals. The primary outcome was change in HBA1C levels from baseline at 52 weeks, looking for non-inferiority of to Zepetide versus additional insulin. Of the participants, just over half were women. The average age was 59 years. The average HBA1C was 8.8% they don't seem to have adopted the international HBA1C levels in these American papers and an average body weight of 90.5kg.
Speaker 1:The results then favored to Zepetide, so the mean HBA1C in that group was 6.7% compared with 7.7% on the Lizpro insulin. That's an improvement in 2% versus 1% HBA1C in those respective groups. This met non-inferiority criteria but was also statistically significantly superior, if that's the right phrase. One suspects that quite a lot of the benefit here came from the associated weight loss. So the group on to Zepetide lost 9kg of weight, whereas those who had the additional insulin gained 3kg.
Speaker 1:And that's a problem that you often see with insulin, which feels really counterproductive to what you're trying to achieve with type 2 diabetes. This is one of the reasons why there was such a surprise amongst diabetes experts that NICE wasn't more favorable for GLP1 analogs. Adverse events were more common in the to Zepetide group and entirely predictable given what we've seen with GLP1 analogs. So primarily gastrointestinal symptoms. But serious adverse events were more common in the insulin group, particularly with hypoglycine emia 48% of people got this on the bolus insulin regime, compared with 12 on the to Zepetide. The authors concluded then that in people with inadequately controlled type 2 diabetes treated with basal insulin weakly to Zepetide compared with pranodial insulin demonstrated greater reductions in HBA1C and body weight, with less hypoglycemia. Could we then see patients ending up on 2 or 3 oral medications plus insulin, plus then a GLP1 analog and whatever other receptors it acts on? Well, possibly, but you do wonder if a better solution may have been that for many of these patients to go on a GLP1 analog in the first place rather than insulin.
Speaker 1:Time now for the next. In our series of interviews with authors of practice changing research, and today I'm joined by Miriam Santa, who is a professor of primary care research at the primary care research faculty in Southampton, and while she does lots of research into patient self care and has done work in other dermatology conditions, this research was on the effectiveness of spironolactone for women with acne, a treatment that has been used, sometimes by specialists over the years, lacking a strong evidence base and certainly hasn't felt like a treatment for general practice. But is it an effective option that we should be considering in primary care and is it a safe option that we can be using? So, miriam, it's great to have you with us today. Thank you so much for taking the time out of your busy schedule to join us. Perhaps you could just start with introducing yourself and explaining why you undertook this research.
Speaker 2:I'm a GP very part-time GP, sorry to say and I'm also a Professor of Primary Care Research, as you said, at the University of Southampton, where I mainly do research and a bit of teaching.
Speaker 2:So why did we do it? Mainly because the NIHR, which is part of the Department of Health and Social Care, put out an advertisement for a team to carry out a trial of a spiral act in acne, or the spiral as some women call it, and I think I'm going to because it's kind of a mouthful. My first thought, I have to say, was that it wasn't really a priority for primary care, and because GP research is so underrepresented in terms of clinical academics, I think it's important we prioritize questions for primary care. But then dermatologist Alison Layton phoned me up to say she thought it was a brilliant treatment, gps should be using it, and she also convinced me that it's a potential win in the war against antibiotic resistance. And then actually, I have to say, since we've done the trial and got a positive outcome and heard the stories of lots of people who took part in it, partly through some qualitative sub-study that we did, I'm actually more convinced than ever that it is actually potentially a really useful treatment for primary care.
Speaker 1:We're always pleased when there's new practice, changing research that is directly applicable to us in general practice. So maybe you could just fill us in with how you conducted the research.
Speaker 2:So I do think it's helpful to talk in terms of the PICO acronym, which is participants, intervention, comparator, outcome, and participants in this trial were women aged 18 or over who had acne for six months or more and whose acne was judged at baseline to warrant treatment with oral antibiotics. It's important to say, I think, that women in both groups were allowed to continue using their topical acne treatments and over 80% of women were actually using topicals at the same time. So the intervention was spiral lactone and we gave people one 5 milligram tablet for six weeks and then two times 50 milligrams, so 100 milligram dose for the remainder of the trial, and the comparator was match placebo. Primary outcome was the acne quality of life questionnaire, which most people won't be familiar with, but it's basically a validated participant reported outcome measure of acne related quality of life and the primary time point was three months. But people in the trial remained blinded to which treatment they were on until six months. We contacted the trial during the pandemic, so it was quite an achievement getting through it.
Speaker 1:That must be quite challenging. Doing anything face to face during the pandemic was very difficult. I'm amazed you managed to successfully do that.
Speaker 2:Yeah, there was all sorts of things going on, like medication being handed over in car parks and so on, but yeah, we got, we got that.
Speaker 1:Participants. They needed a baseline assessment. How often were they followed up?
Speaker 2:Well, they were followed up at six weeks to see whether they wanted to adjust their dose, and then main outcome was assessed at 12 weeks, partly by participant reported questionnaire, like I mentioned, but also a investigator global assessment, so an objective assessment of their acne, and then also again at 24 weeks when they were unblinded, so six months. And then they were followed up again at 52 weeks, but by that point they were unblinded. So it was really more to see what happened to them and who was taking what treatment at that point.
Speaker 1:So this is a study that's for adult women. No men were in this trial, and I guess there's a specific reason why men were not included.
Speaker 2:Yes. So aspiring lactone, as most listeners will know, is primarily used as a diuretic for hypertension, heart failure and so on, but it's also an antiandrogen, which is why it works in acne. But that does mean that it's not really appropriate for men. There was one small trial and I think they had to stop it after they had included about 15 men because of gynecomastia.
Speaker 1:Developing gynecomastia is enough to put a lot of people off, so tell me a little bit about the findings then. What did you discover?
Speaker 2:So we found that on all the outcomes, both participant reported and clinician reported, aspiring lactone did better than placebo.
Speaker 2:Interestingly, the results for our primary outcome, which was the participant reported outcome, showed slightly less strong results at 12 weeks. So at that point they were statistically significant but not clinically significant so that they changed a fair bit, but not as much as what was termed the minimum clinically important difference for that particular outcome measure. But at 24 weeks the differences were quite strong and it's interesting. That might be because hormonal treatments work quite slowly. If you look at trials of combined oral contraceptive pill in acne the difference is a greater at six months than at three months. But it might also be because this up dosing that we did at six weeks. I wonder with hindsight whether we'd updosed sooner maybe after a week or so from 50 to 100, whether we'd have seen better outcomes at three months. And it's interesting, the other ongoing trials in acne are both using higher doses from the outset. So it'd be very interesting when we get their results to see whether actually we should all be using a slightly higher dose from the beginning and getting better results sooner.
Speaker 1:I'm sure that controlling people's acne symptoms as fast as possible would be very welcome, but in fact, with these findings, even if it does take slightly longer, it doesn't really sound dissimilar to the majority of acne treatment. We do normally have to counsel people. It's going to take many months to be able to really judge the benefits. While there were lots of results published in the paper and you can take a look at those in the BMJ there's a nice infographic explaining the key points. One that stood out was the participant self assessed improvement and at 24 weeks 82% of those on Spyro had reported improvement. That compared with 63% on the placebo and almost 20% difference between the two groups is obviously quite important, but actually just the fact that four out of five women reported improvement on Spyro on a lactone, that feels like quite a big win to me. So what then are the clinical implications of these findings?
Speaker 2:Well, I think there's no question that topical treatments remain first line for acne. There's a strong evidence base for them and they do work well if people actually use them regularly for at least six weeks. Obviously, the UK guidelines the nice guidelines for acne haven't changed yet. So second line is generally antibiotic alongside topical treatment. But Spyro lactone is in US guidelines, which is quite helpful because it gives us some of the other information about how to prescribe it and testing alongside it and so on. It's tricky, isn't it, because it's not yet in guidelines. But if somebody said to me, would you rather take oral antibiotics for three months and then stop, or would you rather take something that is not an antibiotic, that's shown to be well tolerated and that you can continue for as long as you need, I think I might actually choose Spyro lactone. So I kind of want other GPs to be aware of it.
Speaker 1:But am I right in thinking that, even if we're not very well aware of it, lots of patients are? Because there's loads about Spyro for acne in social media. I don't do a lot of TikTok, maybe I'm missing out.
Speaker 2:One of the things that we found in the study was that a lot of the participants were already aware of it, again because it's used internationally. A lot of women who took part in the trial said they'd heard of it, so they were really happy to take part and they couldn't really understand why it's not used in the UK and it's hard to say well in the US. The fact that the big studies are not there doesn't seem to matter quite so much to dermatologists.
Speaker 2:It was really interesting. It was one of the findings of the qualitative sub study was that actually a lot of people had already tried to get hold of it and have been unsuccessful.
Speaker 1:I can't say I'm surprised that people have had difficulty getting hold of it if they've requested it, because this is currently not a standard part of UK primary care acne management. But of course your data shows that it is an effective option. I think a barrier for clinicians here may be their experience with Spyro lactone in its more common context of managing heart failure. Here we have concerns around safety and there's lots of monitoring. But of course that's a very different population. That's an older cohort, unwell, comorbidities, polypharmacy and I guess for most people when we're talking about acne management we're talking about a younger, fitter, healthy population. So are there issues around safety in this group and do we need to be doing monitoring?
Speaker 2:Well, this is where it's helpful that it's been used a lot in the US and the US guidelines suggests on the basis of big cohort studies that in women aged under 45 monitoring is not necessary unless they're on other medications such as as ARBs or regular NSAIDs, because it's less familiar in the UK in this population. We did do real function potassium at baseline. We didn't wait for the results before we started the treatment. We just said we'd contact anyone if there was a problem, but actually they were all normal. It was fine. What would I say in the UK? Probably most dermatologists who are using it in the UK at the moment are doing baseline renal function but not doing monitoring after that, unless it's women over 45 or with some other comorbidity or relative relevance, I should say co prescription.
Speaker 1:OK, that's good news. The monitoring requirements for the majority patients will be very minimal. Do we know about the time scales that we should be using this treatment for, particularly? Is there a maximum duration beyond which we should be stopping it?
Speaker 2:It's not such a concern with this treatment. It can be continued longer, which obviously is such an advantage over isotretinoin antibiotics diurnet, where they all need to be stopped after a number of months, and although you know I'd say an important message for primary care is that when people stop antibiotics we've really got to push home the maintenance therapy with topicals to be continued. After stopping antibiotics, some people do still run into trouble, get very frustrated, come back really you know, or just don't want to stop the antibiotics in the first place. So in that situation, do you think spiral lactone has got the advantage that there's no real need for stopping it after a set period of time and for women with persistent acne that's a real advantage.
Speaker 1:One of the things you mentioned in the BMJ was issues around spiral lactone and pregnancy, so maybe that's good to highlight now because, again, that might be another concern of clinicians that might they might perceive as a barrier to prescribing this in this younger population. What do we need to think about in that context?
Speaker 2:Well, it's pretty clear that spiral lactone is less charatogenic than oral tetracyclins, so I think we just treat it in exactly the same way. We would tell people to avoid it in pregnancy, but there's no need for pregnancy monitoring or anything in the same way that we would be doing for ice trend now. So just like a normal medication. I do think for general practice, we probably need to be raising awareness more widely of medications that shouldn't be taken in pregnancy. But spiral lactone, no different from anything else in that respect.
Speaker 1:What next, then? Are there any other areas of uncertainty in this subject that need to be researched, and is there anything else that you're doing beyond this research?
Speaker 2:Thank you for asking. I think the one thing I'd really like to highlight, I think the thing that's so important for primary care is helping people to self manage their long term conditions, and that's what I see as my main research interest. So we are working on an online intervention for Acne to help people keep using their topicals more regularly, because that's such a problem, especially with young people. You know they might use it for a week and then stop, but just trying to try to find ways of helping them to keep using it a bit more regularly. So we're developing that and starting the trial on that soon. It's a little bit similar to our XmaCare online website, which is already freely available XmaCare onlineorguk which has been shown to improve outcomes for Xma. But we're just really keen to do something similar for Acne, because it's all very well prescribing a bit of people don't use it. Then it's not particularly helpful.
Speaker 1:If you've not come across it before, because I have to say it was relatively new to me the XmaCare online website is fantastic, so it's wwwxmaCareonlineorguk and I'll put the link to that in the podcast description. It's really well worth taking a look at Lots of really good, clear information that we can send to patients, and I think when you're managing patients with Xma, if you really want to do a great job of communicating how we do that, it can be quite time consuming. So having something that provides really good information is fantastic. Do check that out, and I'm sure something on Acne would also be extremely welcome.
Speaker 2:We're working on it. We'll get there soon, I hope.
Speaker 1:This has been fantastic. Thank you so much for joining us, miriam. It's been great to hear your insights into Acne management and about your research. Thank you so much for joining us on the podcast today.
Speaker 2:Thank you so much, Neil. It's been a real pleasure.
Speaker 1:Well, I hope you found that interesting. Perhaps practice changing as well. Remember you can always get in touch. So email on hottopics at mbmedicalcom or on X, formerly known as Twitter, whilst it still exists, at GP Hot Topics. Be lovely to hear from you. And if you're a researcher with practice changing, research that's about to be published or recently being published, then please do get in touch with me. Be really interesting to hear from you. And for everyone else, I hope you just have a fantastic weekend. Look after yourselves, take a bit of time, enjoy yourselves and we'll see you on the podcast next time. Bye-bye.