Recorded at the 6th McMaster International Review Course in Internal Medicine.
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Professor Ally Prebtani: Hello everyone, welcome. And I hope you can hear me. My name is Ally Prebtani, I'm an internist and an endocrinologist at McMaster University. I want to welcome the organizers and the participants today. And to thank the organizers for this wonderful, successful international course in internal medicine. And welcome to a nice day – hopefully you are having a nice day as we are in Canada. Before we start, I wanted to just inform the participants that you may submit more questions through the Q&A tab in the Zoom which you are already on. There are also some pre-set questions that I will be going through, that the panelists can answer. So before we begin, I'd like to also just give a brief description of our speakers. I'll start off with Prof. René Rodríguez-Gutiérrez, who is an endocrinologist from Mexico. He will be speaking, oh, he has already spoken, but he will be answering questions related to diabetes. And we have Prof. Hertzel Gerstein, who is a colleague and a friend from McMaster University, who also will be attending to some of the diabetes questions. And there is also Dr. Dror Dicker, who is an internist from Israel, who will be addressing some of the questions related to his obesity presentations. And we have Prof. Leonard Wartofsky, an endocrinologist from Georgetown [University] in the United States, who will be focusing on the thyroid questions from his presentation. And lastly, Prof. Bess Dawson-Hughes, who is from the US – an endocrinologist – who will be focusing on the vitamin D-related questions posed. So we might as well start. There are some questions already that have been identified and I'll start off with the first question. And I do understand that Dr. Dicker has to leave a bit early, so maybe we will start with some of the questions [for] him. So the first question was: “There were some obesity drugs developed in the past, [like] lorcaserin. Are there any other medications right now in obesity that are currently in development?”
Dr. Dror Dicker: Thank you for the invitation and the chance to really present the obesity advances in this field. I think the portfolio of obesity treatment is really very, very exciting. We just had the fourth publication of the semaglutide 2.4 mg, the new drug for obesity treatment, with a very impressive, double-digit weight loss, meaning between 14.9% to nearly 18% weight loss after 1 year. So this is very exciting progress. And I hope the FDA will approve this drug in the next few weeks. The new drugs in the pipeline are the combination drug, meaning the combination between GLP-1 and GIP precipitate, whose results we [can] read in type 2 diabetes patients and very impressive results on weight loss in type 2 diabetic patients, reaching around 12%. But there is now a new program for non-type 2 diabetic patients with this drug, which will affect the effect on weight loss and cardiovascular safety. Now we know that there is another combination between GLP-1 and glucagon. And we know that there is a phase 1/phase 2 announcement on the results of the combination between GLP-1 and amylin. This again is a very exciting development, and we know from phase 1 that after 20 weeks, this combination achieved around 17% weight loss – after only 20 weeks. So this is also a very important and exciting development. But we also know that bimagrumab, a monoclonal antibody against mestotine type 2 receptor showed us that the treatment with this in non-type 2 diabetic patients can really achieve remarkable fat mass loss and a remarkable increase in lean body [mass]. So this took us from concentrating on kilograms to a more functional achievement, a more functional reduction in adipose tissue disease. So I think the portfolio is very, very impressive and gives hope for very successful treatment. But I have to really emphasize, as I emphasized in my talk, that in my humble opinion, the most important thing is not just the weight loss; the most important thing is the weight maintenance, because the yo-yo effect is very, very problematic. So I think these drugs allow us to maintain the achievement of weight loss for a longer time. And this is the most important achievement with these drugs.
Ally Prebtani: Thank you Dr. Dicker. Just on that question again: Are these therapies we have right now for obesity really safe and proven to be safe?
Dror Dicker: I think with the GLP-1 analogue, we have the experience from type 2 diabetic patients. So with liraglutide 1.8 mg, we had the LEADER, study which showed a very impressive advance in preventive cardiovascular disease and very acceptable side effects. So if we increase the dosage to 3.0 mg, meaning liraglutide 3.0 mg – which is called Saxenda – the FDA didn't really need a cardiovascular safety [trial] because of the LEADER trial. And again, the adverse effects were only gastrointestinal. So now, with liraglutide 3.0 mg, we have a 3-year study and in this study we didn't see any problems besides the known gastrointestinal side effects. So I think with the GLP-1 analogue, we have pretty good safety studies and we can really trust those drugs to be safe. For the other combination, we will have to see.
Ally Prebtani: Thank you so much. The next question is for Professor Rodríguez. René, can you comment on aspirin in the use of primary prevention of cardiovascular disease in patients with diabetes? What's the role in the current state?
Professor René Rodríguez-Gutiérrez: Yes. Thank you and thank you all for being here. Yes, that's a very interesting and important question. The use of aspirin has been put into doubt, particularly in primary prevention. I think there is not a lot of doubt that in patients with secondary prevention, aspirin has a benefit. But in primary prevention, the recommendation we have now is that if the patient has over 10% of cardiovascular risk, then there is a need to use shared decision-making with the patient and to talk out risks and benefits. There are some meta-analyses – the more recent [one] included around 10 studies. There is conflicting data regarding benefit in this population, but at the end the important thing is just to talk with the patients about benefits and risks, and in general, the recommendation is [for when] the patient has about 10% of cardiovascular risk in primary prevention.
Ally Prebtani: Thank you. The next question is for Professor Gerstein. Hertzel, “based on the evidence we have right now – in someone with type 2 diabetes, we used to start with metformin – what do you think about starting an SGLT2 or a GLP-1 analogue right off the bat in someone with type 2 diabetes mellitus, rather than metformin?”
Professor Hertzel Gerstein: Yes, it's a great question. I think it depends on why you are treating the patient's diabetes and what your goal is. So, if this person is not that hyperglycemic, but they have diabetes and they have high risk for cardiovascular disease, renal disease then it's a great idea to start them with a drug that's both going to control their blood sugar as well as mitigate their risk of future serious outcomes, such as cardiovascular-renal disease. If they are very hyperglycemic and one of your goals is to lower glucose – and lowering glucose is extremely important because that reduces their risk of eye disease, kidney disease, as well as improves quality of life – then metformin is one of the best glucose-lowering drugs available. And if they also have cardiovascular-renal risk, you could use metformin as well as something else at the same time. If they're lower risk for cardiovascular-renal disease, you can just start with metformin, if they are very hyperglycemic. I think you need to assess the patient and treat the patient and understand why you are treating them and what your goal is. I do not believe in blindly following an algorithm because that's the way somebody wrote it in the guideline. Guidelines are guidelines; they are meant to provide a suggestion and inform your clinical judgement.
Ally Prebtani: I think that's an excellent point. We have to really individualize our therapy: the patient is sitting in front of us and guidelines are just a cookbook. We have to use our brain to sway our decision-making. Thank you so much. The next question is for Prof. Wartofsky. It's a very good question that's been in the literature lately. What is the role of combination T4 and T3 in patients with primary hypothyroidism?
Professor Leonard Wartofsky: So, [it's] a pleasure to be joining all of you here this afternoon, this evening. A very key question – combination therapy for hypothyroidism, meaning treatment with both thyroxine (T4) and triiodothyronine (T3). We just referred to guidelines a moment ago, guidelines being just guidelines. The guidelines of both the American Thyroid Association and the European Thyroid Association waffle a little bit on this question because of the evidence of really clear, evidence-based data. The controversy really has become highly active over the last decade because of the discovery of genetic polymorphisms of the deiodinase enzymes. Deiodinases are the enzymes that convert thyroxine to T3, thereby activating it, T3 being some 10 to 15 times more active than T4. So T4 is the prohormone, if you will, and T3 is the physiologically more active hormone. So the rationale is that when we are giving T4, if there may be any problem with conversion of T4 to T3, wouldn't it be better for these hypothyroid patients to also be exposed to T3 in their daily therapy? The idea is based on the fact that some 20% to 30% of patients who are hypothyroid still complain – particularly if we look at the thyroidectomized population, patients who had an intact thyroid gland and for whatever reason, thyroid cancer, nodules, [or] goiter, had thyroidectomy and then were put on replacement T4 – about a quarter of those patients continue to complain of being tired and not back to their original, pre-operative, euthyroid condition. And there were studies that show that indeed, about 16% to 20% of populations will have this genetic polymorphism of the deiodinase enzymes that could account for deficient conversion of T4 to T3. It's difficult to test for these patients clinically, all over the world, although in research labs one could. So the recommendations have been to do a trial of combination therapy – T4 and T3 – and see if the patients do better on this [treatment]. Such trials are problematic because T3 is very quickly absorbed from the stomach and duodenum and there is no long-acting form of T3. So to really provide T3 in a continuous basis, throughout the day, would require multiple therapies – BID or TID therapy – 2 to 3 times a day at least. And then this adds to non-adherence with the medication: missed doses. So the guidelines of both professional organizations still recommend that we stick to T4 as the primary therapy, but one can take a therapeutic trial of combination therapy in selected patients. How do you select those patients? They would be patients that have a relatively low free T3 value. So that if you measure free T4 and free T3 [and] the free T4 is relatively high and the free T3 is relatively low, you [get] a high free T4 to free T3 ratio. These will be the patients that may benefit from a trial of combination therapy.
Ally Prebtani: Thank you. This is a very hot topic. A lot of patients have come to me, asking for T3 because they can get access to so much literature and stuff online, and the New York Times, etc. So this is a hot topic and it's difficult. Thank you so much. The next question is for Prof. Dawson-Hughes. It's about D2 versus D3, the once weekly versus once daily vitamin D. Any evidence or suggestions on which one should be used for vitamin D deficiency or for bone health? Sorry, you are on mute. You are on mute, Prof. Dawson. There you go.
Professor Bess Dawson-Hughes: There. OK, sorry. D3 gives a higher response level than D2. You can compensate for that by giving D2 – and patients who are vegetarians, for example, will prefer D2 [because] they don't want to take an animal product. Generally speaking, I would recommend D3 for the general population. And the question of dose frequency is a really important one. There is evidence that bolus dosing is a bad idea for increasing the number of outcomes with vitamin D. For example, we have seen bolus dosing increasing the risk of falls. We have seen in recent analyses bolus dosing being ineffective in the realm of reducing infection risk. And it appears that bolus dosing is setting off alarms in the endocrine system. By that I mean the spiking 25-hydroxy D levels that occur trigger an increase in FGF23 which has the impact… FGF23 inhibits the conversion of 25-hydroxy D to 1,25-dihydroxy D, the active metabolite of the vitamin. The bolus dosing also sidetracks some of the 25-hydroxy D from 1,25 to 24-25-dihydroxy D, which is an inactive or relatively inactive metabolite. You can imagine that both of these mechanisms are meant to protect the body against vitamin D toxicity. You don't get that trigger of emergency blockage of 1,25 increases with daily or weekly doses. I don't find any compelling evidence that there is a difference in this realm, between daily and weekly dosing. So I think, as far as we know now, either one is just fine. If I might add one more comment: at least on the bone outcomes, calcium is an essential and important partner of vitamin D in that action. And if your patients are not meeting the calcium intake requirement through food sources and need a supplement, the calcium supplement itself must be given on a daily basis. It is not stored and doesn't carry forward. The calcium you took yesterday is not going to help you tomorrow, for example. Since you have that daily, you might as well take a combination of calcium and [vitamin] D on a daily basis. Just as a practical note.
Ally Prebtani: Thank you so much. The next question is for Dr. Dicker. And this is a question that's often asked. We know that obesity is a real issue, especially in the Western world. And the question is, “When do we start off with the pharmacological therapy versus non-pharmacological therapy versus a combination? How do you stage this process?” It's often a common question asked by patients and other clinicians who work in this field.
Dror Dicker: It's a very important and very difficult question, but my belief – and the literature supports it – is [that] obesity is a chronic relapsing, advancing disease, meaning it's a chronic disease; it's for life, there is no cure. So this is maybe the second sentence in the discussion with my patients because it's very important to really emphasize that the treatment is for life. You can't start to treat an aim to weight loss and then forget it and regain the weight and then go back and try to lose more weight, so we really should aim to build a program that if patients can adjust to diet and physical activity for life and lose and maintain at least 10% of weight, [then] this is an excellent solution for them. The issue is that only 5% in Israel and I think 6% in Canada, as we learned from the ACTION study in Canada, maintained at least 10% for at least 1 year by just changing lifestyle. So, really, the majority of patients could not maintain at least 10% weight loss. And then we have to add pharmacotherapy. Now, as I showed in my talk and as I just explained, we have very effective pharmacological tools now to reach this 10% weight loss and to maintain it as long as the patient is taking the medication. The problem is that the patient does not really understand that obesity is a chronic disease, like diabetes. If patients have diabetes, they really acknowledge that they have to take the medication for life and if they stop taking the medication, the diabetes will re-appear. So in obesity, we have this problem and we have to explain the patients that they have to take the medication for life and [that] when they are taking the medication, they can really control the weight loss. As we see in the STEP studies – now with the semaglutide 2.4 – with the SELECT study and other studies, with the LEADER studies, when you are taking the medication, you maintain the weight loss. And if we see all the other studies with other medication, like metformin or the other combination of Xenical (or orlistat), after 4 years they still maintain considerable weight loss. So if we don't reach this, the patient will regain weight after treatment by pharmacotherapy and lifestyle changes. Or if the patient [has a] BMI above 30 and diabetes, without the option to control his diabetes, or if he has a BMI above 35 or 40 with other comorbidities, [then] we have the option of bariatric surgery. Now, bariatric surgery is a game-changer too, because we know that after bariatric surgery – according to our experience and our publication – you can reduce total mortality by 50% after 4.2 years in diabetic patients. So I think we have an algorithm [with which] you can really tailor the solution for the patient. First of all, and this is the baseline for every treatment, is lifestyle accommodation and change after the pharmacotherapy, after a bariatric surgery, or we have now endobarial or gastroscopic options for treatments that are not surgery. So this is my algorithm.
Ally Prebtani: Thank you, Dr. Dicker. The next question is addressed to probably both Prof. Rodríguez and Prof. Gerstein. And maybe we will get two perspectives and hopefully they'll be the same, but also some variety is nice, too. So the question is, “In a patient with type 2 diabetes mellitus, how do you choose between an SGLT2 and a GLP-1 analogue? How do you make that decision? Whether or not they're on metformin?”
Hertzel Gerstein: Who would you like to go first, Ally?
Ally Prebtani: Maybe just to keep things in order, René? Do you want to start off?
René Rodríguez-Gutiérrez: Oh, sorry. I just got []. What was the question, Ally?
Ally Prebtani: So the question is, “In someone with type 2 diabetes mellitus, how do you make a decision whether to use an SGLT2 inhibitor versus a GLP-1 analogue? Whether or not they're on metformin?”
René Rodríguez-Gutiérrez: Well, that's I think a difficult question. It will depend again on the individual patients. I think for secondary prevention, if a patient has heart failure and the atrial infarction [is] below 40, then probably an SGLT2 inhibitor is better. And also if you are looking for renal protection, then also SGLT2 inhibitors have a proven benefit. Then probably that's a better idea. On the other hand, if you are on the primary prevention side, then that's more difficult because actually the talk that I gave, Challenges in Medication, and that is very challenging, right? Because it will depend a lot also on the economic aspects, comorbidities, accessibility to the medication, [and] convenience – because a lot of patients just don't want to inject themselves. So both can reduce weight. Probably a GLP-1 receptor agonist more than SGLT2s. Both have a cardioprotective effect; both are easy to take. We have GLP-1 receptor agonists that are once a week, once every day, [and the same] with SGLT2 inhibitors, once a day, so it's very easy to take them. So I think on the primary prevention side, you just have to talk with the patients, see what the patient wants, in my opinion, and when I talk with patients, for a patient it's always easier just to take one pill once a day. They kind of, at least in Mexico, they don't like the need to inject themselves. But I have patients that feel very comfortable using a GLP-1 receptor agonist once a week. So I think it depends a lot to see the patient as a whole, with all the comorbidities that a patient has and also to see the social, financial, [and] family context of what the patient wants and what he or she can really do, because at the end, some of them are very expensive. I mean, both medications are very expensive, but probably GLP-1 receptor agonists a little bit more [so]. So it doesn't make a lot of sense just to give a medication that the patient, when he comes back at 3 months, he cannot continue taking. So I think it has to be a commitment to knowing that the medication has to be continued and I think the best thing is just to talk with the patient and make a decision together.
Ally Prebtani: Thank you, René. Hertzel, do you want to give some comments?
Hertzel Gerstein: Sure. Yes, I think once again it's important to understand what your goal is in treating the person. So if your goal is glucose lowering and they have renal insufficiency, forget about the SGLT2 inhibitors because SGLT2 inhibitors are not going to lower glucose very well if the GFR is 40 or 50. But they still have major renal protective effects, so if your goal is renal protection and they've got a low [GFR], then an SGLT2 inhibitor will be my first choice because they are the best renal protective therapies, period – in diabetes and non-diabetes. The best renal protective therapies ever invented were … SGLT2 inhibitors. But for glucose lowering with the lowest GFR, you are not going to get much benefit. That's a very important point to make. The other one is, if a person has had anything to suggest that they're at risk for heart failure – in addition to the renal question, a risk for heart failure – then I would tend to use an SGLT2 inhibitor. If they've had any sort of stroke in the past, ischemic heart disease type of picture, then I would push more toward a GLP-1 receptor agonist. GLP-1 receptor agonists seem to have particular benefit towards fibrovascular disease based on the meta-analyses of all the GLP-1 receptor agonist outcomes trials. So, that would be the general way of thinking, in addition to all the things that were already mentioned by my colleague. The only thing that I'd point out is that meta-analyses of both the GLP-1 receptor agonists and the SGLT2 inhibitors show there is no difference on their efficacy in either primary or secondary prevention populations. And I don't think it's actually useful to really think of people in primary versus secondary prevention. I think it's better to think of people… to try to estimate a person's risk of having a cardiovascular event. Primary or secondary prevention is short-hand to say well, if they're primary, they haven't had a previous event, they're at low risk; if they have [had] one, they're at high risk. But that's not true; there are lots of people who have never had an event [but] are very high risk because they have every single risk factor around. So really, the evidence is that I think you … the higher risk they are, the more they're going to get a benefit from a risk reduction therapy. But meta-analyses show no interaction between primary [or] secondary and the effect of either the SGLT2 inhibitors or the GLP-1 receptor agonists. So I just look at the risk. That would be my approach.
Ally Prebtani: Thank you. Just on top of that, the kidney… we know that we've gone quite a long way with renal protection, you know, blood pressure control, glucose control, RAS [renin-angiotensin system] blockade. Even now some of the MRA data that's been around, but that's for another day. So who is really at risk of renal disease? Is it the GFR? Is it the microalbuminuria? When do you really want to consider an SGLT2 inhibitor? That's a common question.
Hertzel Gerstein: The GFR is, you know, the most important index of renal function. I mean, you actually know what the person's renal function is. And if the GFRs are over 40, and a year ago it was 50 and 2 years ago it was 60, you know that you have a problem. Albumin-to-creatinine ratio is definitely a risk factor for renal insufficiency; there is no question. And you know, the various classifications of kidney disease look at both the albumin-to-creatinine ratio and GFR and they classify people according to those. But obviously, the lower the GFR, the closer you are to having an important renal event. But albuminuria is certainly a risk factor for [one] and it's a reason to think of renal protective therapy. So that's the short answer to the question.
Ally Prebtani: Thank you very much. The next question is for Prof. Wartofsky. Prof. Wartofsky, this is a common question and it varies with guidelines, nation to nation, continent to continent. “Should all pregnant women be screened with a thyrotropin or TSH and thyroid antibodies, in particular TPO antibodies?”
Leonard Wartofsky: Well, that is a controversial question, as you know, Ally. American Thyroid Association guidelines would say yes, certainly TSH level in the first trimester and if there is any suggestion that it is higher than accepted, then to follow that up with a repeat TSH and thyroid antibodies. The American Association of OB-GYN, to the contrary, does not agree – and perhaps it's somewhat political, I won't go into that – but on the basis of just rationality, given the risks of even mild or subclinical hypothyroidism in pregnancy, there is good reason in my view to screen with the TSH level. [It's] a simple test, easily done [and] inexpensive. And once one appreciates that the value was a little higher than it should have been, to follow up and repeat it within 3 or 4 weeks with antibodies, recognizing that the TSH in the first trimester of pregnancy is lower than in the non-pregnant state due to the production of HCG from the placenta – HCG being a thyroid stimulator, [it] stimulates release of thyroid hormone, which in turn suppresses TSH. So the normal or reference range of TSH in the first trimester is lower than usual and that should be appreciated, so that a range of perhaps 0.1 up to 1 would be what one would see in the first trimester and an otherwise normal TSH of 3 or 4 would be distinctly elevated for the first trimester and would warrant further examination.
Ally Prebtani: Thank you, Prof. Wartofsky. The next question is for Prof. Dawson-Hughes: “There has been a lot hype also in the media and some literature about using high-dose vitamin D to protect against cancer and autoimmune disease. Can you comment on that?”
Bess Dawson-Hughes: Yes. High-dose [vitamin] D … let's say, in autoimmune or infections has been pretty much documented as a bad idea. If we were to look at infection, which comes into play in regard to the role of vitamin D with inflammation and other alveolar activities, the high-dose D was found to be the source of heterogeneity in an individual participant level meta-analysis of the highest quality, in my view, by Adrian Martineau. This was published in 2019. In 25 trials looking at vitamin D to impact infection rate, there was large heterogeneity and it was attributed directly to the bolus dosing, or high-dose D. Among those in this meta-analysis who received daily or weekly vitamin D dosing, there was overall a 20% lower risk of developing an infection. And within that dosing regimen, in those with 25-hydroxy D levels that were very low – less than I think it was 10 ng/mL – there was an exaggerated benefit. In contrast, in the bolus dosing group of trials, they were null with respect to infection. So vitamin D, in addition to influencing inflammation, increases cathelicidin, which will target infected epithelial cells. You know that the enzyme paraphernalia within lung epithelial tissue is such that 1,25[-dihydroxyvitamin D] can be produced. And so, we have a direct mechanism and we have an important finding there. Martineau and his colleague, Jolliffe, very recently published an updated meta-analysis with 43 instead of 25 trials. But this was not an individual participant level analysis, which is sort of the top of the quality chain; it was just a trial level analysis. And they found a reduction with daily and weekly vitamin D supplementation, but it was not 20% – it was on the order of 8% and that difference may be related to the degree of quality with which you can examine the data in a trial level versus participant level analysis. So I think vitamin D… we do know that it dramatically increases fall risk, fracture risk. In that classic Sanders trial with an annual bolus dose, it was disastrous in terms of increasing falls and fractures. So I mean, the handwriting is on the wall here to absolutely avoid bolus dosing. Several years ago, I was trying to teach the fellows about how to replace a patient with [an] extreme vitamin D deficiency and we took on the assignment of trying to find the evidence that the rapid replacement, bolus dosing approach – you know, the 60,000 units twice a week for 3 weeks, then go to maintenance, that kind of strategy – [but] we could not find any compelling evidence for benefit there. You can get the 25-hydroxy D level up a little bit, but no one has really looked at what happens to the 1,25 D in that scenario. So my teaching now is [to] avoid it; just put them on the maintenance dose straight out of the box and don't run the risk of locking the 1,25 production or increasing its rate of metabolism, because that's actually what you are aiming for is to get the 1,25 up. So thank you.
Ally Prebtani: Thank you, Professor. It's just in the absence of evidence, sometimes, I think they are done in different ways. It's really very interesting, the practice of bolus dosing vitamin D, which we often see. The next question is for Prof. Rodríguez. René, a common practical question. You know, we have a lot of non-insulin options these days, but sometimes we just don't get to the hemoglobin A1c that we want to get to. When is the right time to really take that pen out and prescribe insulin?
René Rodríguez-Gutiérrez: That's also not a straightforward answer. I will say, right now, as you said, we have a lot of potential medications with a low risk of adverse events. Usually, and again, as we have said, the guidelines are just a way to… know them, not necessarily to follow them. But at some point, maybe when you have used 3 medications, and then an important aspect that changes – as we have known for years that the first injectable to be insulin, but now that has changed and actually what most guidelines recommend is a GLP-1 receptor antagonist. So when you are not on goals and on 2 or 3 medications, then the first injectable that is actually considered in most patients [is] a GLP-1 receptor agonist. And then if it doesn't work, you can go to basal insulin. Of course, again, that depends because if the patient cannot buy the medication or has no accessibility to the medication, maybe when the patient is not on goal – a glycemic goal – and there are 2 or 3 medications, then you can go to insulin. If that's a patient that you have been seeing chronically. On the other hand, if you [are seeing] for the first time a patient that is catabolic, that has a hemoglobin A1c probably over 10, then probably [at] the beginning it's not a good idea just to start on the insulin; probably a combination of oral agents. So basically, that would be probably my approach.
Ally Prebtani: Thank you. I think one thing that you stressed a lot is being very sensitive to cultural and local resources, because it does really vary from country to country and even in our backyard in certain populations. So I think that we should be very careful with the resource limitations that exist in many, many areas before prescribing any therapies that may or not benefit that patient. Hertzel, do you want to comment on this initiation question? Any other comments or thoughts?
Hertzel Gerstein: I think, obviously, if there is any question or uncertainty that the person might have type 1 diabetes, then they should be put on insulin right away. I think… even if it's a low dose, then that's important. Other than that, if somebody presents and they are very hyperglycemic and their hemoglobin A1c is very high, there is nothing wrong with starting them on insulin; you can always stop it later on. It is an effective therapy to control, you know – especially if they're very symptomatic with hyperglycemia – to get their glucose under control. You can start other drugs at the same time or you can get them under control first and then stop insulin. Insulin has been clearly proven. It is not an addictive drug; you can stop it at any time. If anything, good control for a period of time with insulin might have a value to stop it and keep good control without any therapy or with minimal therapy afterwards. That's old data and it's also recently been reprised. We know that insulin does not increase the risk of any of the consequences of diabetes except for hypoglycemia. That's it; that's the only side effect of insulin. So it's a safe and effective drug and if you are treating somebody with uncontrolled hyperglycemia, it's the one that you know is going to work. And so my big message to people is “don't be afraid of insulin.” Insulin has been proven to be safe with large, international randomized trials. [There is] no question whatsoever, it does not cause any problems. It doesn't prevent any problems, either than those related to hyperglycemia. The only side effect is hypoglycemia. And weight gain with insulin, by the way – people are always worried about that – in big trials we are talking about 1 kg, 2 kg, etc. Not the anecdotal stories. But we have lots of alternatives now. And insulin can be used temporarily. So use it when you need it.
Ally Prebtani: Just on top of insulin, in terms of insulin secretion, is there any role, Hertzel, for sulfonylureas in 2021 going forward?
Hertzel Gerstein: Sulfonylureas have a lot of baggage with them, but they are also… interestingly enough, they don't increase the risk of any other consequences of diabetes, either. And that's less competent to say that, but it's based on 2 trials that together are reassuring about the long-term effect of at least the second-generation or the third-generation sulfonylureas that are out there. Having said that, sulfonylureas do one bad thing. It's that they tend to burn out the pancreas, to speak of it metaphorically. In other words, randomized trials have shown that if you treat somebody with diabetes on a sulfonylurea versus some other therapy, their degree of deterioration in glycemic control over the course of a few years will be faster because they lose the ability to secrete insulin more rapidly compared to other therapies. Having said that, that was shown with the older sulfonylureas; we are not sure if that happens with the newer ones. So I have, I use sulfonylureas, but not often. We have so many other alternatives. All things being equal, I prefer not to, but there are certainly some patients who benefit from it and they can take it long-term, especially the second- and third-generation ones like gliclazide. In Canada, that's the one that we use most commonly. In the United States, glipizide is another one that's used, and glimepiride. Those are the 3, I think, that are out there. But they've now gone lower down in my list of tools that I use to treat people with diabetes. By the way, there are still thiazolidinediones and they also have a place. These are cardioprotective drugs, at least pioglitazone was shown [to be] in a large trial and the meta-analyses of all these TZD drugs show that they reduce ischemic heart disease. But they do increase fluid retention and [in] some people there is this pulmonary edema problem. But in selected patients – not many, it's also low in my list, in my toolbox – but I certainly occasionally use a thiazolidinedione in some patients.
Ally Prebtani: Thank you, Hertzel. Again, going back to resource limitations in the World Health Organization, there are 3 drugs for diabetes: they are DPP4, metformin, and sulfonylureas, because of the availability and sustainability. It's really easy for us to prescribe a GLP-1 analogue if we could take it to Uganda or wherever, but it might just for a month and when you leave it's all gone. So I think we have to keep that in mind. The next question is for Prof. Wartofsky and this is an interesting question, more on an in-patient basis, we get this periodically. The concept of Hashimoto's encephalopathy in that patient who is in hospital, admitted to neurology or internal medicine with no obvious cause for their encephalopathy. Can you comment on that concept of Hashimoto's encephalopathy?
Leonard Wartofsky: Yes. It's a mysterious disorder and there is again some controversy whether this is simply 2 disorders: Hashimoto's thyroiditis, being a very common disorder, and a patient with coincident neurodegenerative disease presenting with positive antibodies. Is this so-called Hashimoto's encephalopathy or not? There are some older studies that suggest an autoimmune basis that just [like] the autoimmunity against the thyroid, there is an attack of vessels in the brain with deposition and decreased blood flow. The clinical presentation in these patients is typically one of either multiple small strokes or of a progressive dementia. And of course, the differential diagnosis for that includes many entities with negative anti-TPO antibodies or the absence of Hashimoto's disease. In both clinical presentations, seizures can be prominent. And perhaps a trial of moderate- to high-dose steroid therapy is warranted in the absence of any other specific therapy, with the hope that this may be of an autoimmune basis. But the data to support that are really quite thin.
Ally Prebtani: Thank you Prof. Wartofsky. And the next question is for Prof. Dawson-Hughes. It's about vitamin D, a 2-parted question: “Is it important to repeat vitamin D levels when you supplement someone with vitamin D? And number 2: Is there a role for screening for vitamin D deficiency?”
Bess Dawson-Hughes: The US Preventive Services Task Force weighed in again recently on the subject and they came in agreement with the IOF and many other organizations in that the screening and follow-up measurements have been way overdone in many parts of the world. The recommendation for people at general risk to meet their nutritional requirement is 8000 units, above a certain age and, you know, using the IOM recommendations. There is no indication for screening levels or follow-up measures in a general medical practice, unless there are extenuating circumstances of a given patient. And such circumstances would be, for instance, an absorption problem that could stem from, you know, any malabsorption or inflammatory bowel disease, anything that would affect the absorption of vitamin D – which occurs throughout the GI tract, but largely in the distal ileum. So conditions affecting that area would be applicable there. In patients with osteoporosis, for whom one needs to be especially vigilant, I think if you have an osteoporotic patient with a low level, it's quite reasonable to do a follow-up measure just to make sure you are on track there. Many of these patients will be getting no sun exposure and very little [vitamin] D in their diet and so forth. So I think the role for measurement has been exaggerated in recent years and I think we need to get this under control, because it's running up medical costs, it's causing a lot of churning, and it's not adding any compensatory value. So I think that answers both questions, basically. Do you need a measurement at the beginning: no, not except under unusual circumstances. And do you need a follow-up: no, except under unusual and designated circumstances.
Ally Prebtani: Thank you very much. Next question to Prof. Gerstein. Hertzel, can you comment on the role of DPP4 inhibitors/gliptins in terms of type 2 diabetes mellitus? What's their current role, being neutral in terms of cardiovascular disease?
ertzel Gerstein:H Well, they are neutral for cardiorenal protection, for sure. And really, the way to think of them – I think I also answered the question online – is that they make metformin lower glucose better than it does on its own. Metformin is a good glucose lowering drug [and] metformin in combination with a DPP4 inhibitor lowers glucose even more. Most jurisdictions have combination pills around and the advantage is you actually get, at least in Canada, I think you get a better quality metformin when it's in the combination with the DPP4 inhibitor, because it's made by one of the proprietary pharma companies etc., etc. But the major benefit is [that] when you need a little bit more glucose lowering and metformin alone is not doing it, the combination with metformin and a DPP4 inhibitor is a very simple approach to do. And there are really no side effects that you need to be concerned about, with one exception. One exception. It's rare, but, you know, when GLP-1 receptor agonists came out, everybody was worried about the risk of pancreatitis with GLP-1 receptor agonists – and that has not materialized. All of the RCTs, the large outcomes trials, have measured that as a side effect and have not seen any increased risk in that or pancreatic cancers or anything else. But actually, the meta-analysis of the DPP4 inhibitors does show a slightly increased risk of pancreatitis with those. So, I would not use a DPP4 inhibitor in anybody who has ever had any pancreatic anatomical problems that would raise the concern for pancreatitis. But other than that, you know, the drugs are very easy to tolerate and go nicely with metformin. That would be the approach.
Ally Prebtani: Thank you. René, do you want to comment on that in terms of DPP4 inhibitors, on top of Dr. Gerstein's comments?
René Rodríguez-Gutiérrez: Pretty much I agree with the answer. Pretty much, if you are looking just for glycemic control and you cannot get to target, then they are very useful. I mean, they are not very potent, but there are, as Dr. Gerstein said, very low side effects, pretty much [none] and we have been using them for years. They are more accessible in many countries. So I think they are a good option. Of course, if you are looking for renal, cardiovascular and all the things we were [talking about]: weight and some others, then you have other options for sure.
Ally Prebtani: Thank you. The next question is for… Dr. Dicker has left. I wanted to thank him for his contribution. Moving on to Dr. Wartofsky again. Dr. Wartofsky, there are a couple of comments from the questions about gluten and celiac disease. Any association between Hashimoto's and gluten insensitivity and celiac disease? Any comment there, please?
Leonard Wartofsky: Well, just that there is clearly an association. And this can become problematic when we get back to the issue of the effectiveness of thyroxin therapy and [whether] patients are having some GI problems that are impeding absorption of their thyroxin or not. The presence of a whole number of autoimmune disorders are of increased frequency with Hashimoto's. So whenever one sees coincident potential endocrine disease, you can think about this as a true association. For example, the original classic was perhaps Schmidt syndrome, of hypothyroidism due to Hashimoto's with adrenal insufficiency, but there can be ovarian insufficiency, testicular insufficiency, and of course celiac disease. So with symptomatic GI disturbances, it's worth referral to a gastroenterologist and evaluation for celiac disease. And then appropriate management thereafter when seen in a patient with Hashimoto's thyroiditis.
Ally Prebtani: Thank you, Prof. Wartofsky. The next question is for Prof. Dawson-Hughes. It's about a patient who was on a drug holiday after using bisphosphonate [], they were taken off the bisphosphonate and the bone density significantly dropped. What would you consider next?
Bess Dawson-Hughes: That is impossible because I don't know the patient's history and I don't know the necessary details to give you an intelligent answer. In general, from what came across, there would be no contraindication that I would know of, to returning the patient to alendronate. Alendronate is highly effective, it's the least expensive of the high-quality options for treatment, but beyond that, tailoring, choosing other drugs would depend – as Hertzel has pointed out for your diabetes choices – on a lot of detail in the particular patient's case. I would just make a comment that there is emerging evidence and push on the part of a number of leaders in the osteoporosis field to perhaps get away from the idea that you would start a long-acting bisphosphonate drug initially and then resort to the newer and more expensive bone-forming agents as in sequence there. And that for patients who come to attention who are at very high risk for osteoporosis, it makes sense to start with a bone-forming agent first, get this big step up in bone mineral density, and then start a maintenance or an anti-resorptive drug second. That would put a drugs like alendronate in second and longer-term sequence with an agent like a parathyroid hormone or, you know, denusomab. Any of the forming agents to come first. That will, I think, trickle its way into osteoporosis guidelines in the future. It is not quite there yet, but that is where things seem to be heading.
Ally Prebtani: Thank you. The next question is for Professor Rodríguez. We all like to use a multi-faceted approach to management of type 2 diabetes mellitus in terms of risk reduction. Can you comment on the role of icosapent ethyl, one of the newer omega-3 fatty acids that's being marketed? What's its role in type 2 diabetes mellitus for cardiovascular prevention?
René Rodríguez-Gutiérrez: So if I remember correctly, there is a recent trial published in the New England Journal of Medicine that it showed a reduced risk of cardiovascular events but I don't think it's very available, at least to my knowledge, it's not available in most countries. So I haven't used it particularly. So I don't know, if I heard it OK, but it's probably the fatty acid that reduces triglycerides and that [it is] the first medication that has demonstrated a reduced cardiovascular risk in this setting but I think probably to my knowledge, it's very expensive. So I don't have really a lot of experience with this medication.
Ally Prebtani: Hertzel, do you have any comments, additional comments?
Hertzel Gerstein: Yes, you know, it was the REDUCE-IT trial, that was the trial you were referring to, Ally, which showed that it does have cardioprotective properties on top of everything else. And when added to the therapy, it takes a while to start to see anything in the REDUCE-IT trial. The Kaplan-Meier curves did not diverge until 2 years [had] passed. So it really does not work right away; it's a long-term effect. But I think it's a tough one because it starts to raise the question of how much pharmacotherapy you are going to give your patient and when does it become a point that… you know, there are a lot of diminishing returns because every time… Let's say you use cardioprotective drugs and each one of them reduces the risk of a cardiovascular event by about 20%. So statins, you go 0.8, then you add a GLP-1 receptor agonist, that's another 0.8, so that's 0.64. Then you add another, you have an SGLT2 inhibitor, let's say that's another 0.8 – I mean, you know, to [keep it] simple – so then you get 0.43. And you get to a point where there is a flattening of the curve, right? So, you know, there comes a point as well [to ask] how much more are you going to add to a person with the burden of drugs versus the actual risk. Now, people are very high risk and… if somebody is hypertriglyceridemic, you know, because of genetic [or] other reasons, that is a reason to choose one of these drugs, because you'll lower triglycerides as well as having a true cardioprotective effect. And you reduce your risk of pancreatitis, [which] goes along with high triglycerides. That's something which is a reasonable thing, but in the absence of that, then I think it becomes [an issue of] where you want to put it on your cocktail, you know: statin, SGLT2 inhibitor, ACE inhibitor, maybe an aspirin a day, you know, depending on what the risk is. And then maybe ezetimibe – like how far do you go? And then that becomes the question. Do you have [another question] on top of that?
Ally Prebtani: Yes, I know that's conundrum these days: aspirin, rivaroxaban, colchicine. Just trying to extrapolate but…
Hertzel Gerstein: Yes. And there is also evidence of ticlopidine in people with diabetes, you know, as an anti-platelet drug. And it's the same sort of story, right? And often the cardioprotective therapies that we use are often the ones that we are comfortable with. A cardiologist uses a different suite of drugs than an endocrinologist does, even though we're both doing cardioprotection, you know? And coming from a different way. So I think that is sort of part of the art of medicine.
Ally Prebtani: Thank you so much. Prof. Wartofsky, I'm sorry for asking you all the controversial questions, but they're good questions. Maybe you want to comment on desiccated thyroid in the use of… You probably knew this was coming?
Leonard Wartofsky: Yes, no surprise. So, desiccated thyroid is generally porcine thyroid and is a gemish of various iota proteins and both T4 and T3. And what kind of evoked a little more interest in desiccated thyroid in the last few years was a study from the Naval Hospital in Bethesda, [MD], USA, using desiccated thyroid and showing that patients did better in terms of their SF-36 questionnaires, their weight loss and weight maintenance, and a few other clinical parameters. And they raised the question of whether desiccated thyroid has not gotten a bad reputation over the years. Part of that reputation was due to the fact that its shelf life is not as long as thyroxin, so that with only a very small market share of prescriptions, the preparation might stay on the shelves in the pharmacies longer and be less potent. And in addition, because of its T3 content, particularly in elderly patients – with T3 being absorbed very quickly with a sharp increase – elderly patients complained of headache and even perhaps angina from cardiac ischemia in the first 2 hours after ingestion. So these were reasons why endocrinologists [and] thyroidologists advised against desiccated thyroid, in that thyroxine gives you a slower and safer conversion of T4 to T3 without that bolus T3 effect that is available from desiccated thyroid. Coincident with that bolus effect, of course, is that patients would describe a little increased activity, a little bit of a buzz from the T3, that many of them liked. And therefore preferred – on a subjective basis – taking desiccated thyroid. But by and large, guidelines and most endocrinologists do not recommend desiccated thyroid. We all have patients who swear by it, and like Charlton Heston and his rifle, you can't get their desiccated thyroid out of their dying hands.
Ally Prebtani: Thank you. We have a time for one more question, for Prof. Dawson-Hughes. Is there a role for calcitriol in vitamin D deficiency or in bone health?
Leonard Wartofsky: I think she may have had to leave, Ally.
Ally Prebtani: OK. That's fine. I think we're actually on time. Thank you so much. I just wanted to thank all the speakers for their wonderful replies to outstanding questions on the participants. And it was very fruitful session. I learned a lot. It's always quite interesting to make it so interactive and virtual is the way to go I guess at least for the next a little while. And I wish everyone a safe day and a safe week. And I just wanted to mention that there are 2 more sessions that will still come ahead, live sessions. So please, continue to join us. And thank you so much to all the speakers.
Leonard Wartofsky: Thank you for a great job moderating. Terrific.
