Fresh Updates and New Developments in Diabetes Management
Dimitri:
Welcome everyone to the latest instalment of our Rural Health Webinar Series. My name is Dimitri and I will be hosting tonight’s webinar. This webinar will explore emerging new evidence based on international and national guidelines on diabetes management. It follows on from a previous Rural Health webinar series on diabetes recorded in December last year.
Tonight’s webinar is facilitated by Dr Gary Deed. Dr Deed is a GP based in Brisbane. He has a passionate interest in promoting quality care for patients with diabetes in general practice and is involved with education, policy development, research and collaboration. He is the Chair of RACGP Specific Interest Diabetes, and a member of the RACGP Quality Care Committee.
I would like to begin tonight’s webinar by acknowledging the traditional owners of the lands that we are coming together from and the land on which this event is being broadcast. I would like to pay our respects to their Elders past and present, and would also like to acknowledge any Aboriginal or Torres Strait Islander people who have joined us this evening.
Before we begin, a few housekeeping things to cover. So you will notice that you are all on mute, and that is to ensure that the webinar is not disrupted by any background noise. We do encourage you to use the chat function or Q and A function to ask questions. When using the chat function, we do ask that you address your questions and comments to all panellists and attendees, rather than just the panellists, so that everyone can see your questions and comments.
And finally, tonight’s webinar has been accredited for one hour of Educational Activity CPD hours. To be eligible, you must be present for the duration of the webinar. We also kindly ask that you complete the short evaluation at the end of the webinar. It should only take a few minutes to complete, and will help us to improve the format and content of future webinars. By the end of this webinar, you will be able to apply updated knowledge on the indications of diabetes therapeutics, such as sodium glucose transporter 2 inhibitors, discuss management approaches to younger patients diagnosed with type 2 diabetes, including risk reduction, review varied presentations of diabetes and differentiate diagnosis such as maturity onset diabetes of the young, and latent autoimmune diabetes in adults, and discuss how technology can be implemented in a clinical setting when managing diabetes.
But for now, I am going to hand it over to our facilitator for this evening, Dr Gary Deed.
Dr Gary Deed:
Thanks, Dimitri, and thanks everyone for joining us tonight on a wonderful early winter evening. There are my conflicts of interest and disclosures. I do clinical work like many of you out there. I am also involved in some national and international projects and research projects as well. I have worked with the pharmaceutical industry across a broad range of educational and policy development.
I am going to start with this case study. We have got a fair deal to cover, you know, those wonderful learning outcomes, so I hope you can get a gist of what we are getting through tonight, and remember, I am also going to provide these slides for you through Dimitri and the Rural Faculty after this, so do not be concerned about getting too much detail down now.
Jane is a patient, a 29-year-old teacher of South Asian family origins. She is married with a child, five years, and works in a regional city here in Queensland, actually. But had gestational diabetes. But she has come in because she was told to return because of a high glucose that was found on recent testing. She has got hypertension. I should say three years ago that was diagnosed, she is on Telmisartan 40 mg. Mild myopia. Does some yoga, only once a week and socially drinks on weekends. So, not highly active which is part of people’s busy lifestyles. As doctors, we want to look at the patient. There was not any cardiovascular abnormalities, but her blood pressure was 140/80, and that is while she is on Telmisartan. Her weight and height, interesting the BMI was 28.1, and in people of South Asian origin, we know that of course that would be classified in the obese range, not overweight. If of European background, that would be overweight, but certainly South Asiana people, we take the cut-off point a little bit lower. Note the cholesterol as well, LDL 2.3, is it a target? It is something that we probably would put through cardiovascular risk calculator, although she is a bit young actually to put through the risk calculator according to ones that are available. But, there has been an update of the Heart Foundation Risk Calculator coming out probably in another couple of months. So, look out for it. It is much more expanded and it allows you now to include things like family history and other things, it actually changed the accuracy of the risk calculators that we have been utilising the last few years. Notice her fasting glucose is 7.3, haemoglobin A1c of 6.5%, and hopefully you know that in the models we will go through about how to make a diagnosis of diabetes in a moment, but remember she is largely asymptomatic. In people that are symptomatic, a single abnormal blood glucose of that level or a haemoglobin A1c of 6.5% or higher is diagnostic, you do not have to repeat it. But in people that are asymptomatic, we will get to that in a moment.
She is basically a young adult. She is only 28, but it is you know, I have been working for how many years now, so more than 30 years, and I had recently had a patient who was nine, who we diagnosed with diabetes, but it was actually type 2 diabetes. So, diagnosing diabetes in young adults, I will get to that in a moment, but the criteria is similar and exactly the same as adults, but we have to think about other factors that might be overlapping with young adults when we diagnose diabetes.
Right down the very bottom, it is very important not to miss type 1 diabetes, because that can develop into a metabolic crisis very quickly, and many people with type 1 diabetes unfortunately present with diabetic ketoacidosis. I had another child recently who I was doing some pathology on for another reason, and their glucose was elevated on random glucose testing, but I thought I would not accept that as the person had eaten food. We repeated it and actually we picked up a type 1 diabetes very early. They had not gone into metabolic crisis and they were very strongly positive as you may know with GAD antibodies and insulinoma or IA-2 antibodies. I think that was in the thousands, so it was a really good pick up and I felt great about that. And those are mostly positive in people with type 1 diabetes, however there are 10% of people with type 1 diabetes, where they do not have antibodies, so it can be a little bit confusing. Always think about the metabolic presentation, weight loss, highly symptomatic polyuria, polydipsia et cetera.
What I am concerned about is also in young adults under the age of 30, particularly, that there are forms of diabetes like latent autoimmune diabetes of adulthood, which still can apply to this group, where there is a rapid autoimmune destruction of beta cells, and these patients have a very distinct pathway, where you might have started type 2 diabetes oral medication and they quickly reveal themselves as not really responding to that therapy. One take home message I need you to remember is about MODY, or monogenic diabetes. This is where there is a really strong autoimmune dominantly inherited family history. And often they are younger patients, and even many people think that they are type 1, but in fact, it is really about taking a really good family history when you do diagnose diabetes. It can also rarely occur in older adults, but mostly before the age of 25. And some of those cases and actually, many of the cases, do not require insulin, and do require specialist assessment and genetic testing. So look for it, genetic clustering in a dominantly inherited fashion.
I want to mention that there is a guideline that was presented. So, Dan, I will get to you in a moment at the end about what is a GAD antibody. Someone has asked a question. That is an autoimmune antibody that attacks the beta cells and the islets of the pancreas, so depletes insulin production, and it is also insulinoma antibodies as well, so it is a really good marker. The only other marker that GAD is attracted to is for stiff man syndrome, where you do not have the other islet antibodies, but that is a very rare condition, but I have seen one case in my primary care career.
This guideline is out. So this is published in the Medical Journal of Australia. There is also a General Practice Consensus Document to help you understand, really looking at there is a rising number of type 2 diabetes in young adults, arbitrarily we say from 18 to 30 years of age, and we do not want to miss things as I said, like type 1 diabetes. The diagnostic criteria is the same as the adults, except that you should be thinking much more clearly about the possibility of MODY and also type 1. And in fact, in addition, if you do have a patient between those ages that may be type 2, we still recommend that you consider doing antibody testing to be absolutely certain.
The problem with antibody testing, is it may take a week or two for it to come back, so if there is a metabolic crisis, you need to manage it. But remember also that we are trying to ask you to think about high risk individuals that you may see in your practice, overweight or obese, younger patients, you know, people are pregnant and had prior gestational diabetes. High risk ethnicity groups which are present and clearly articulated in this document and will be also in the handbook of Diabetes Management by the RACGP. The problem with people like Jane, they often have a very aggressive disease trajectory, with development of cardiovascular disease very early in life, and remember they are going to have to live with diabetes, I mean, she is 28, and she is going to live with diabetes now for another 60 or 70 years, and the accumulation of possible complications may be a problem, just because of the time course of the illness, but also, we believe that vascular protection is important. So it is very important to reduce risk, even though some of the studies and some of the medications that we are using, we are going to talk about in a moment are very much useful in this group, it is very important to look at lifestyle factors and also if they are overweight or obese looking, that is risk factor modification.
Remember, you are very involved in developing team care plans and facilitating care for these patients. It is very important for young people, probably to at least have some specialist assessment, be it from an endocrinologist or a general physician as well as yourselves, but also remember, credentialed diabetes educators, cardiologists appropriately et cetera are important.
This is from the handbook on diabetes, about when you have an asymptomatic patient, how do you go through the testing? Well, I am not going to go through this in detail, this is from handbook, the RACGP handbook, but it is important that if you do get an abnormal result, which is a fasting blood glucose over 7, for instance, or a random glucose over 11.1, or particularly, haemoglobin A1c over 6.5%, it is very likely they have diabetes, but repeat the test. So, in Jane’s case, I repeated the test to confirm the diagnosis, because she was largely asymptomatic. What happens is there can be discordance. Some people can have an elevated fasting glucose and elevated A1c that is maybe 6.4%, and you say, well do they have diabetes? Repeat the abnormal result. You do not have to repeat both necessarily to have a true diagnosis. Remember, in newly diagnosed diabetes, some people do have a honeymoon period where their blood glucose levels take a little while to become destabilised. So, it is important to repeat and be very clear about the diagnosis and monitor them appropriately, which is possibly the three monthly haemoglobin A1c.
Someone said, how do you diagnose LADA? Well, LADA is diagnosed both clinically with a rapid deterioration failure of usual type 2 management, or often they have a positive antibody test as well. So they are not true type 1, they are type 2. And MODY of course, if you have a strong family history and you are actually thinking it is MODY, get them off to the specialist endocrinologist who will be able to do appropriate genetic testing as well. It is important because the treatment options are very varied and very specific to the type of MODY that is diagnosed.
When are you going to repeat the test? Well, the repeat test usually, if they are not symptomatic, you could repeat the test within a week. You do not have to wait for the haemoglobin A1c. If the haemoglobin A1c was say 6.7%, as in Jane’s case, you are allowed to repeat that even under a three month period for a true diagnostic criteria. I believe you can do one week, but I would not be leaving it months, because you know, they could develop metabolic crisis as well. I do not do GAD and IA2 antibody testing for newly diagnosed diabetes in say a person who is 45 years old with multiple risk factors, but what I am saying is, people under the age of 30, are particularly at risk of being missed as having some of these other types of diabetes. But remember, MODY can occur even a little bit later in diagnostic frameworks and ages as well. Let us keep moving.
What can you do as GPs? I mean, we are talking about diagnosis. I need you to go back and I mean, this webinar is not just about diagnosing diabetes, you go back and look at that criteria about be certain about how you do it, symptomatic versus asymptomatic. Think about selective patients who you might do antibody testing on appropriately. But new diagnosed people, even Jane, I mean, is diabetes remission possible? And we are going to talk about that in a moment, yes it is, but you need to understand what sort of patients are possible to get remission in. Remission is, well I will give the definition in a moment. But also, how weight management can apply across people with diagnosed diabetes, particularly. But then we are going to go through to how to individualise therapy and phenotype individualising.
So, type 2 diabetes remission is defined as sustained improvement in haemoglobin A1c, where for instance, Jane got levels below the 6.5% for at least three months in the absence of glucose lowering medication. So, it is not a cure, but it is actually saying, these people do not need to have medication. And there is guidance, how do you achieve that in a patient? Well, there were clinical trials which showed this is the famous DIRECT study, which is a UK study done in general practice, where they achieved remission on diabetes within the 12 months. So you can see that it was based around weight loss. And in fact, when you achieved 10% to 15% weight loss, and certainly above 15%, you had a high chance of creating true diabetes remission in newly diagnosed patients. Now, phenotype of responders is very important. They were newly diagnosed, that is, they were under six years post-diagnosis. So a person who has got 18 years post-diagnosis, the ability to get them into remission might be much harder. Certainly, people using insulin, because they have had metabolic crisis, it might be much more difficult. As I said, over 10% body weight reduction was probably ideal. But the problem with this too, is that only 30% have remained in remission at two years post intervention. So, the numbers needed to achieve remission seem to be high, and it is quite an intensive program, but I am not saying we should not at least try, all right?
Someone has just asked. I will answer the question about LADA and insulin. We do not call it insulin dependent diabetes mellitus anymore, it is called type 1 diabetes mellitus, because insulin dependent diabetes can be type 2 as well, but we will come back to that question at the end. Sorry about that.
So, what we are talking about is weight management. If you can achieve weight management early in patients where weight management is appropriate such as Jane, there is an obesity management algorithm that has been published by the Obesity Society and the Australian Diabetes Society, and it is looking at how you can achieve that through application of reduced energy and very low energy dietary replacement and also pharmacotherapy. I certainly do not have the time to expand on all of those options, but we will go through some of that just quickly here. Even moderate weight loss may not achieve remission, but may improve cardiovascular risk factors such as blood pressure. And also if we take it out of the diagnosis of diabetes, but people at risk of diabetes, it reduces their risk as well. And in that algorithm it talks about the currently available TGA anti-obesity medications, none of which are PBS subsidised, and they go across a range there. And hopefully you have got some experience using them and of course, semaglutide is the new party, but it has not been released as a pharmaceutical obesity medication at the present time. Wegovy is the trade name. Remember about very low energy diets et cetera, but also you need a supported multidisciplinary program.
This is to remind you that progressive weight loss improves the metabolic sensitivity of people with diabetes, and other people without diabetes too, and particularly around organ-related and insulin receptor related factors, but also inflammation. So we are trying now to look at greater amounts of weight loss to achieve not only remission, but improvements in metabolic factors in patients.
As I mentioned, Wegovy or semaglutide is now approved in Australia, but remember it is a different dose regime for weight loss versus the management of diabetes which is 1 milligram. It is a maximum weekly dose for people with diabetes for glucose management but the doses for obesity will go up to 2.4 milligrams. Nausea of course is a problem with the GLP-1 receptor agonists as well, and remember, if you are using it for weight loss, even off label, these are category D, so you must ensure the patients do not fall pregnant while on these medications, and even be off it for three months before even contemplating it. Or give appropriate contraceptive advice.
I want to mention that there is a product coming, which is now a GLP-1 receptor agonist and a glucagon intestinal peptide, which is the two what we call incretin peptides that are produced by the intestines that act on the pancreas as well. But the dual combination appears to have dramatic effects on weight loss, well above the single GLP-1 receptor agonist. So, here is a modification of the effect of anti-obesity drugs. And remember we are looking for minimum 5% weight loss versus placebo, and you can see you know, some of the agents we use in the Australian market, phentermine, naltrexone, bupropion combinations are on there, but semaglutide, look at that, 12.5% from a published study, but this new twincretin, 20% weight loss was seen in the recent clinical trial, which is equivalent to bariatric surgery.
Alright. So we talked about diabetes remission, the importance of phenotyping the people we can try to achieve it, but also trying to focus on weight loss. I know I am moving quickly, but we are just going to move through some of the newer evidence in diabetes around some of the other aspects of managing diabetes, which are cardiovascular disease, particularly heart failure, but also other forms of cardiovascular disease, but also chronic kidney disease. And that these are interlinking, non-separable cardiometabolic and renal dysfunctions. Interestingly, also, a lot of people do not realise that people with COPD mostly die of cardiovascular disease as part of the illness. So it is interesting. So, cardiorenal, pulmonary, metabolic, this interplay of metabolically inflammatory conditions that go hand in hand.
So when you are managing a patient with type 2 diabetes, I want you to think beyond just the glycaemia, but you, yes, glycaemia is very important for microvascular disease, and we do not want to ignore it. So, haemoglobin A1c tracks that, and it is important to have a good monitor on that, and patients at target. But you know, we all know the big macrovascular complications of diabetes are really significant across the spectrum. Remember I talked about young people with diabetes, ages 18 to 30, they develop some of these macrovascular and microvascular problems very early, and it is very important to start to be wary of those patients and look for cases that you may have.
So, the new paradigm and the new evidence is the fact that we are trying to not just address glycaemia, because each of these medications I mention here do address glycaemia, but they do other things. We call them non-glycaemic pleotrophic effects, which were found actually by accident, by serendipity in the cardiovascular trials that were mandated because we were concerned that some diabetes medications may actually harm patients. They found that they had inadvertently, for instance, empagliflozin in the famous study, showed that it could reduce the risk of cardiovascular death in patients with established cardiovascular disease. Amazing result. Then with heart failure, they also found that initially with people with diabetes, and now people without diabetes, an exposure to the SGLT-2 inhibitors, through complex mechanisms, they appear to be able to manage symptomatic heart failure. Interesting, the TGA indications for empagliflozin are a bit broader, the effect is independent of left ventricular ejection fraction. The TGA indication for dapagliflozin is for a reduced ejection fraction. But, in the PBS prescribing of those, so I just want to be very careful here, these are TGA indications, but in the PBS prescribing, they are only indicated with or without diabetes for left ventricular reduced ejection fraction heart failure. I put in the brackets there that the eGFR for the use of empagliflozin for heart failure is anything over 20, and dapagliflozin over 25. But if you are using them purely for diabetes management, the eGFR for empagliflozin is anything over 30, and dapagliflozin, they are suggesting over 45 to have clinical glycaemic lowering effects. But to remind you that the effects on the heart extend down lower. So, these are non-glycaemic benefits at lower eGFRs.
So, look at chronic kidney disease. They also then found that dapagliflozin for instance reduces the risk of progressive decline in kidney function in adults with proteinuric chronic kidney disease where the CKD-2, 3, 4 and ACR greater than 30.
Other benefits are also being shown across the GLP-1 receptor agonists. When you look at it, it is a very important study here that looked at a network meta-analysis where they are trying to compare studies by correlating the different types of patients and comparing them. It is a very powerful way of analysing things, rather than just look at single studies. And this study here by Lin and Lee et al, showed that the SGLT-2s and GLP-1 receptor agonists reduced the risk of MACE, that is a term which is Major Adverse Cardiovascular Events, deaths from all causes, hospitalisation for heart failure, and composite outcomes of renal events. It was not just the SGLT-2s that now they have seen in clinical trials, but the GLP-1 receptor agonists as well.
Importantly, the GLP-1 receptor agonists were also superior for reduction of stroke. But the SGLT-2s were stronger in lowering hospitalisation for heart failure and renal events. So it is interesting, even though combined together, they appear to have this global sort of non-pleotrophic effects, they have some differences in their mode and target of action on clinical outcomes. Very importantly, when they looked at the studies, and this is not being pejorative against certain patients, but these are because the studies included these patients, that efficacy appeared higher in elderly patients, Asian and white populations, because they are more included in the clinical trials. But very importantly, the greater power appears to be in people with pre-existing disease and longer diabetes duration. So I am trying to get in your mind that phenotype of how we utilise those with the greatest effect, without just throwing drugs randomly, you are trying to perform precision medicine.
So, we talk about guidelines. So, based on this emerging evidence, in Australia, they have developed something called the Living Evidence in Diabetes Guideline to bring that data together into something that would help you, and a lot of people have not even seen this, but it is an NHMRC approved guideline. It is very succinct, because they have not had an ability to look across multiple other areas at the present time. They had a look at the evidence, and they still believe that Metformin has what we call a conditional recommendation as a first line therapy, which I think most of us would agree. Conditional means that the evidence is old, and it is maybe not as strong as some newer evidence, but it is still a positive recommendation. But here is the other recommendations on the SGLT-2 and the GLP-1 receptor agonists. They believe that you should consider the addition of an SGLT-2 to other glucose lowering medications, where there is cardiovascular disease, but also, people with multiple cardiovascular risk factors and / or kidney disease. And then you may consider a GLP-1 receptor agonist if the SGLT-2 is not tolerated or contraindicated. So, they are putting the SGLT-2 ahead of the GLP-1 receptor agonist because the evidence is stronger. But then, they still say, you could use a DPP-4 inhibitor as a conditional recommendation. When you are unable to prescribe a SGLT-2 inhibitor or a GLP-1 receptor agonist due to intolerance or contraindication. But interestingly so, they have a conditional recommendation against using a sulphonylurea as the first choice of medication to add to Metformin in dual therapy, because of the increased risk of severe hypoglycaemia. Interesting as well.
Okay. I will just keep going. I know there is questions coming through, thank you for that. I will not go through this, this is embedded in our handbook, and this is just to show you the step-wise sort of progression, and you know, how you add Metformin and SGLT-2s et cetera to combinations. The problem is, in this step-wise diagnostic pathway, you cannot add a GLP-1 receptor agonist to a DPP-4 inhibitor, because they are working on the same pathway. And the other thing is, you cannot add a GLP-1 receptor agonist to an SGLT-2 inhibitor or a DPP-4 under the PBS, because it is not funded. Just be wary to understand the PBS when we are prescribing. However, outside of the PBS, international guidelines say that the combination of a GLP-1 and SGLT-2 has some evidence behind it, but the PBS currently will not support the combination and be paid for.
Goodness gracious. This very complex slide is the Americans, who love complexity and try to get everything on one page. So, I am not here to go through some of the detail on that, but what I am really saying is that even international guidelines, not just national guidelines, are now saying that it is about individualisation of choice. And with that, I will just enlarge that a little bit and show you that. What they are saying, if you have got a patient in a left-hand column who has got ASCVD, atherosclerotic cardiovascular disease, if they have got that, then the pathway is consider either a GLP-1 receptor agonist or an SGLT-2 inhibitor. If they are at higher risk, the same pathway applies, and they actually define high risk for you, as patients over 55 years of age with two additional risk factors such as obesity, hypertension, smoking, dyslipidaemia, or albuminuric chronic kidney disease.
Then they also phenotype patients with heart failure, and suggest that if they have got heart failure, consider an SGLT-2 inhibitor as a first addition to be added to their therapy. And with CKD, and currently proteinuric CKD, consider an SGLT-2 inhibitor. And if it is not tolerated or contraindicated, consider a GLP-1 receptor agonist. See how I am trying to show internationally and nationally we are trying to phenotype patients.
When you are just worried about glycaemia, do not forget that there are other methods of managing them, and do not forget about the Metformin and combinations, including insulin, which may be required in a patient where glycaemia targets are important for microvascular risk reduction. And you can combine insulin with some of those other agents we have just talked about before. And also weight management goals, because they believe that is important and they obviously have prioritised the GLP-1 receptor agonist as a priority.
Now, what other guidelines are there? Do not get too concerned as I said I will share this slide. But this is the Heart Failure Australian Guidelines released this year by my friend Andrew Sindone et al. And, the top green is what you need to remember basically and going, we do not have a lot of time to focus on heart failure alone today, but it is really that there are now four pillars of treatment. In the past, we knew that beta blockers, mineralocorticoid agents, were used and also ACE inhibitors and or ACE and ARNI inhibitors. But, now, they are saying that the SGLT-2 inhibitors are part of the four pronged approach to managing patients with heart failure. And they go through about if your patient presents congested versus eucvolemic, what order to add them to. So do not forget now there is also now PBS approved prescribing, that is available for patients with and without diabetes, and you can utilise them for the management of heart failure, but go and look those up and please think about them. A patient with heart failure that are not on an SGLT-2 inhibitor, I need you to ask yourselves why they are not on that at the present time, and there may be some reason for they are contraindicated, such as a failing, very, very low CKD with an eGFR say less than 20 or 30, but otherwise you would have to ask yourself the reason why that is not included, because the evidence is strong.
Let us move on. We have got a lot to cover and I know that I have been talking a lot. I am sorry about that. But we are talking about Jane, and remember I said she is young and she is going to live for maybe another 60 years, and we want to certainly manage microvascular disease. And microvascular disease might be retinopathy, so I do suggest you know, she needs very careful recalls and planning and optometry and ophthalmology assessment. Certainly if she does develop retinopathy, there is evidence of course for fenofibrate for the secondary prevention of progression. There is very low evidence of fenofibrate for prevention of retinopathy, but it is therefore progression of retinopathy once it develops. And of course, when there is macular and other types of retinopathy, the ophthalmologist may use the injectable antiVEGF therapies as well. So do not forget that and I am sure you have got patients who are receiving some of those things. Certainly it is general practice’s role to consider fenofibrate 145 mg per day, but if they are on a statin, just be careful of very low risk but potential risk of myopathy.
Nephropathy of course, remember now I emphasised about the importance of the guidelines on heart failure and SGLT-2 inhibitors, but do not forget about the emerging evidence of SGLT-2 inhibitors for chronic kidney disease. And again, not just in diabetes patients. Certainly now limited to proteinurea, but just watch this space, there may be further developments.
Do not forget about lifestyle. Of course smoking cessation is very important, the A1c, but also bloods and lipids as well.
Macrovascular, that is very high in our mind. I said, please use a risk calculator that is appropriate to our patient’s presentation, and I mentioned about the Heart Foundation developing a broadened, more practical cardiovascular risk tool. So watch this space, probably coming by November. Everyone knows of course, lifestyle are the same factors that we talk about microvascular disease and the importance of statins. The importance of treating to target. If a patient is at risk, you know, the LDL has a target to lower to less than 2 for instance, but if there is a presence of existing atherosclerotic disease, getting that LDL down lower is very important. And now everyone is pushing for combination therapy with the statins, certainly as a trial et cetera.
Do not forget about the SGLT-2 inhibitors as part of risk reduction and considering the choice if appropriate for the patient. Remember there are potential problems in some women with higher instances of genitourinary mycotic infection, so watch for that. And also watch the fact that SGLT-2 inhibitors need to be withdrawn prior to major surgery for at least three days, or minor surgery for 24 hours before, because the risk of euglycemic DKA. The GLP-1 receptor agonists of course can also be utilised to help manage risk factors as well, and once of the side effects of those can be weight loss as well. But look at the TGA indications and the PBS criteria when you are combining things.
I want to mention also emerging is another agent called icosapent ethyl, and you may not have heard about that, but there is a very famous study that emerged that was studied in patients with macrovascular disease and diabetes, who had persistent hypertriglyceridemia above a level of 1.7 mmol per litre. With this agent, which is coming to the Australian market, had evidence of reduction of major adverse cardiovascular events. And used in combination with a statin. So, this may be a new combination agent but I would like you to just keep up to date and know what is coming around the corner. But you will see it emerge.
I am going to switch hats, because we are getting through this. But I wanted to talk about technology, which is one of the learning outcomes that we talked about. And it is a huge area, but you might have seen some of your type 1 patients using pump therapy et cetera. Now of course, the use of pumps requires a lot of advanced knowledge. I actually do not manage pumps myself, although I have done a lot of work in this area and worked on guidelines, because I think it requires a lot more time and effort that I believe I can afford to do. And the guidelines suggest that it should be done under a specialist team based approach, and using a credentialed diabetes educator who understands pumps. Some CDEs do not, and they do not do pump therapy, but also a specialist endocrinologist or diabetologist who has specific interest and knowledge of those, because they can be quite complex, and now there are things called closed loops where sensing devices are developed that can transmit to the pump et cetera, giving it information on how to manage that. If you want to learn it, I think there are some courses around that and they are important. But I think more importantly is also what we call CGMS, which means continuous glucose monitoring systems, and that is emerging as something useful for GPs to be aware of. One type of continuous glucose monitoring is a flash glucose monitor, which you know, I do not like to use trade names, a Freestyle Libre is one where it is a monitor which is worn for two weeks which can send glucose information to a smart phone App, and it allows you to monitor the glucose variability and time in range, which I will show you in a moment. It can be applied to people with type 2 diabetes. It is not funded by the government, only for people with type 1 diabetes, or some people with forms of pregnancy related diabetes. So it can be costly, but for instance, if you are starting insulin, it might be useful to help have the patient understand what their insulin and what their glucose is doing, and also helping watch for hypoglycaemia. And you can do it for a short period of time and gather this information. I utilise it extensively, and offer it to patients. Some cannot afford it, but it is certainly something you should be aware of.
I do want to say to you, this is an article published in Nature I think in 2021, is technology will set you free. Well, let us be wary of blanket statements such as that. You know, I was saying, I utilise it in patients, but it requires a lot of translation of how to utilise the technology and make it work for the patient. It is not like, just plug it in and it is all easy to go, and it requires a bit of time and your effort, but technology is emerging. There are a lot of new Apps et cetera, and I think as GPs, we need to bring ourselves up to speed or else we are going to become dinosaurs in diabetes, let alone other areas.
One of the things that you might need to develop is, there are courses around now about how to read the read-out from these glucose monitors for instance. This is not a pump monitor, this is a glucose monitor, and there is the number that appears when the person flashes their glucose, but there are also arrows that tell you the trending. So, is the person going high? Or say if that level came back at 4, if the arrow was pointing down, are they going to go into a hypoglycaemia soon? But also, see on that wave graph on the right-hand side in the blue and black, it is something called time in range. You can see is this person tracking within a particular bandwidth we call it, bandwith of glucose. We are trying to look at people to stay in target range probably over 70%, it is called glycaemic variability of bandwidth. These are some of the things that are emerging.
I am sorry I have not answered your questions yet, but I am getting close to the end and hopefully I can answer those. And just to remind you, is it freedom? These technologies are costly. Alright, there is monthly costs and then set up costs and then ongoing costs. So, are they the doyen, are they going to change diabetes management for everyone? And really, I mean, I am an advocate for people with you know, across the social determinants of health, and some people just cannot afford it, and you know, we need to advocate for non-technological approaches, use the medications we have, and other lifestyle factors in a better way.
So goodness, I have thrown a lot at you today, but I hope you have got a little bit out of it. I just want to sum up though. I went through a lot of evidence around how to phenotype your patients’ presentations. And do not forget that you will get these slides afterwards, so you will be able to read through and get a bit more detail in your mind about how you, when you are individually managing patients, how do you think about, should I use an SGLT-2 inhibitor? You know, have they got atherosclerotic disease, so should I ramp it up? Should I use it for heart failure of chronic kidney disease, et cetera. I do want to remind you that early onset diabetes in overweight or obese, consider weight management and pushing for diabetes remission, but not all people will be able to achieve that. VLED means very low energy diets and meal replacements. And whether a GLP-1 receptor agonist is something that you should consider, or even when they become available, the new twincretins which have a greater efficacy.
Microvascular complications. We do not want to give up on haemoglobin A1c. Think about CKD and the emerging evidence around SGLT-2 inhibitors. I mentioned about fenofibrate and retinopathy. Macrovascular complications, lifestyle, physical activity. Statin and combination agents are rarely the bees knees now. I mentioned this icosapent ethyl that is emerging as well. So keep your eye out for that. We talked about heart failure and SGLT-2 inhibitors as being very potent. But remember, what I have got in brackets there are the TGA indications, but the PBS only currently supports use in reduced ejection fraction heart failure. There is evidence of cardiovascular death in empagliflozin with people with existing cardiovascular disease, so I mean, that is a hard endpoint. I think that cannot be underplayed. Do not forget about the stroke risk reduction, and people with diabetes have a 72% increased risk of stroke. Technologies are changing. And of course, do not forget to become part of the RACGP specific interest group if you can.
Wow, you know, I have worn myself out. But let us go back and answer some of the questions. So, Donna, you asked, how do you tell the difference between type 1 diabetes and LADA if they both have positive antibodies and need insulin? Most people with LADA probably do not need insulin early on. People with type 1 diabetes usually need insulin right from the get-go. They often have that metabolic crisis presentation. So, a little bit of a different presentation. But if you are uncertain, get the specialist endocrinologist to help you sort that out. That is where I would going. Okay?
Dan asks, it is awkward when starting someone on semaglutide, is it available again? Actually, semaglutide should be coming available. I have a lot of patients who are now saying they can get it quite easily, but they do have to shop around. You have to take them off the SGLT-2 inhibitor due to PBS funding. How do you manage that? That is a big issue. Some people may consider funding the SGLT-2 inhibitor privately, and have the FLP-1 receptor agonist on the PBS, because it is not PBS subsidised, so I think that is not against the rules. However, I warn you that the PBS and PBA see a change in the guidelines for the GLP-1 receptor authority listing and it is going to get all of us in a bit of a knot, because they are actually going to make us ring for the initiation of a GLP-1 receptor agonist forthcoming, and we are going to release that news soon unfortunately. And also, there is going to be tighter regulation around the use of GLP-1 receptor agonists and combinations as I mentioned, because people have been using them willy-nilly and not according to PBAC restrictions. So, watch this space. We will tell you that through the RACGP channels. Maybe happening in the next two months or so.
Is it worth starting metformin in a patient with impaired fasting glucose and obesity? Certainly lifestyle in the diabetes prevention trials, very famous trials, lifestyle interventions which are intensive lifestyle and dietary change did perform better than metformin in reducing the progression to diabetes from pre-diabetes. And, that actually worked better in people with impaired glucose tolerance versus people with impaired fasting glucose. Interesting, isn’t it? That postprandial glucose rise appears to indicate probably better metabolic response to lifestyle and also metformin. But if you are going to use metformin, it performed a 31% reduction in progression over five years versus 58% with lifestyle. I would consider it, but remember it is a bit off-label because it is labelled for use in diabetes, so if you are using PBAC, please do not, it is dirt cheap anyway, so patients probably will not be out of pocket too much.
Roz asks, is it okay to use an SGLT-2 in an 80 to 90-year-old? Roz, I do think it can be appropriate as long as, remember chronic kidney diseases emerges and eGFR falls especially over 65 in people with diabetes. So, it is possible that you could utilise that, although the numbers in clinical trials are low. One of my concerns with people over 80 and 90 utilising SGLT-2s is that they have a partly lowering of blood pressure effect and combine that with a possible dehydration, you could potentially cause hypotension. So just be gentle about the use of those and carefully check the eGFR and make sure they are not dehydrated and certainly not on additional diuretic therapy which would aggravate that.
Thalia asks, if a patient has a good glycaemic control, and has heart failure, can we add an SGLT-2 as it will help both? You certainly may, and you may prescribe it under the alternative PBAC listing. So you do not have to use it for the diabetes listing. So, that is where you can combine them, and in that listing there does not seem to be a contraindication to combining it with a GLP-1 receptor agonist. Interesting, isn’t it?
Zaid askes, are cholesterol targets different between average and high-risk groups, or are they the same for everyone? I sort of divided it up between people with existing disease versus those that have cardiovascular risk factors. So, it is really currently being seen as you know, do you have the disease yet or do you not? But remember, coronary artery calcium scores that show suppressant of significant coronary artery calcification would suggest they have got the disease so the target has to be lower. That might be a person when they do not currently have symptoms of course. So, existing disease versus those that do not, or at high risk, and those at high risk, we would target LDL at around 2, but going lower, even down to 1.4 with existing disease.
What is the recommendation for alternative glucose control when you need to cease SGLT-2s for surgery or colonoscopy? Huge problem. You have to take them off it. It is interesting, the washout effect of SGLT-2s may take about three days, so sometimes they do not get into a hyperglycaemic crisis. Most patients with type 2 diabetes do not get into metabolic crisis quickly if you have got their A1c under reasonable pre-operative management. So really, you need to be thinking ahead and try to get the A1c certainly closer to 7% before surgery, so when you remove the SGLT-2s, they do not get into a crisis. Otherwise, short acting basal insulin may be acted, maybe an additional thing that you may need to think about.
Due to recent issues with semaglutide, many patients, this is Thalia again, have changed to insulin. What would you do if your patient has all other types of oral drugs and Lantus insulin in the morning, but has a high pre-dinner blood glucose level? I would certainly as you say, manage the dose of the other oral agents. I would certainly consider going back on an alternative, dulaglutide or semaglutide. I would not necessarily remove the Lantus insulin. You can add Lantus, which is a type of glargine insulin by the way, that is a trade name, glargine insulin basal insulin, to a semaglutide, and get effect. But I would reduce the dose of the glargine or basal insulin by 20% at least, but do not stop it when you add the semaglutide. I would not necessarily add a pre-mix or a co-formulation insulin. I think because the semaglutide allows you to get the benefit of blunting the weight gain effect from the insulin that you are using, but also getting post-prandial and also basal insulin affect adding to the basal insulin. So that is what I would do. Or add dulaglutide.
Fewar asks, impaired glucose tolerance 1 point below the diabetes mellitus level, morbid obesity, moderate comorbidity, started metformin. Can they go on a GHP-1 receptor agonist? You have to be certain that they have got diabetes. So, I would suggest that if you keep monitoring them closely, the glucose will allow you probably to prescribe that within the next few months. But please, you have to adhere to the criteria, that is, have a haemoglobin A1c above a certain level. Read the PBS criteria.
Is there any preference or accuracy difference in requesting fasting blood glucose, random blood glucose, haemoglobin A1c? Each of those capture a different Venn diagram. So, the number of patients in the fasting glucose group that are abnormal versus the impaired glucose tolerance versus a haemoglobin A1c, the Venn diagrams, they are not equivalent. They are slightly different. So, capturing different groups. In fact, the most sensitive diagnostic test is actually the oral glucose tolerance test. If you look at sensitivity and specificity, you know, how many people really like that? The next most sensitive is fasting blood glucose, and the next one is haemoglobin A1c, you know, in ranked order. So, fasting glucose levels in the absence of oral glucose tolerance, this might be your most sensitive.
Getting there. Is Wagovy, which is semaglutide for weight management and obesity, available for weight reduction without diabetes? No, it is not yet on the market. It is authorised by the TGA, but is not yet being marketed unfortunately.
Are there other medications you might be able to use in insulin resistance in those who cannot tolerate metformin? Certainly, yes, the SGLT-2 inhibitors and GLP-1 receptor agonists do have insulin sensitising and weight management effects which improves insulin tolerance. But look at the PBS criteria to see how you can combine them. If you cannot use metformin, you might have to combine it with a very low dose of a sulphonylurea. The PBAC are not aligned to the evidence based guidelines, they are purely guidelines filtered through a funding filter, unfortunately.
Getting there, almost there. I cannot do all of these, but I am just trying to look. The SGLT-2s lower eGFR initially. That is very true. It is not a pathological lowering, it is purely a physiological lowering and you might have to wait about a month before being concerned about that lowering. So do not start an SGLT-2 and do an eGFR within the first couple of weeks of starting it and say, oh my God, they have lowered the eGFR, it is purely a physiological reduction. If it is lowered after a month more than 20% of the initial, then you might be concerned. But most patients will tolerate it.
What are your thoughts on using Rosuvastatin in those at risk of diabetes? Well, there is a small elevated risk of creating a risk of diabetes by using a statin, especially a high dose statin, so you have to watch that. The trouble is, the risk factors for developing diabetes are also risk factors for hyperlipidaemia and what do you do? Do you lower the risk of cardiovascular outcomes or do you worry about a small but you know, not insignificant but small risk of developing diabetes. It is something you have to talk to your patients about.
Should all type 2 have metformin in their drug regime if tolerated? Yes, they should, because of insulin sensitising effects. There are other non-pleotrophic effects of metformin that I have not talked about, and it is worth putting metformin and non-diabetic benefits and you might alarm yourself to learn something about metformin there, so I will leave you with that.
Are GLP-1 receptor agonists safe in the elderly? They are actually safe in the elderly up to probably, I mean, they are not extensively used in people over the age of 80, again because they are not included in clinical trials, but they can be used in the eGFRs, right down to eGFR of 15, so you do not have to worry about the renal issues as well. I think we are getting close to time, Dimitri?
Dimitri:
Yes, we are. We are almost at 8:30, so yes, we might unfortunately have to sort of end it there. Gary, thank you so much for such a great webinar, obviously by the number of questions that were coming through, I am pretty confident that everyone is very engaged and has learnt a lot. So, a reminder to please complete the evaluation that will pop up in just a moment when the webinar session closes. It really only takes just a couple of minutes to complete. Certificates of attendance will become available on your CPD dashboard within the next few days, but for any non-RACGP members who would like a certificate, please email rural@racgp.org.au. And of course, do not forget to tune into our other three monthly webinars which are held on the first Thursday of every month. And on that note, I will end the webinar for everyone. Thank you again, and have a wonderful evening.
Dr Gary Deed:
Bye.