Good afternoon. Thank you for coming and joining us for this session that we are going to go over some of the studies and data and some practical tips about post-transplant diabetes mellitus. Why this is important? Because we know that post-transplant diabetes in transplant recipients causes increased risk of graft loss, contributes to cardiovascular events, and all-cause mortalities. So this brings the importance of understanding the risk factors and management and early intervention. The data and information in the literature is confusing due to the fact that some areas places pre-existing diabetes into the same pot as post-transplant diabetes, which is indeed a new diagnosis after transplantation. Previously, when I was giving this talk 20 years ago, we would call it NODOT, which was new onset diabetes after transplant. We see PTDM up to 30% of kidney transplant patients and even 40 or more percent of liver transplant patients. And this is, again, the data that might not be that clean because of the lack of consensus on diagnostic criteria and including pre-existing diabetes in these percentages. It is also important to note the risk factors so that we could intervene early to prevent the PTDM from advancing and causing harm to the patients. Older age, which is a risk factor already for a type 2 diabetes, is also a risk factor for post-transplant diabetes. Being a male is a disadvantage. Sedentary lifestyle is a problem, and this is a problem for, I think, all of us as physicians as well. We are very sedentary, as much as the rest of the world. It looks like 30% of the world currently is not meeting the exercise guidelines recommended. Obesity and being overweight is a risk factor. In the United States, one out of five individuals currently is obese, so the obesity is a big problem and a contributor to post-transplant diabetes. Gestational diabetes is also, to have a history puts you on a higher risk. Of course, family history, which is not a modifiable part of us, can put us in a pot of increased susceptibility due to genetic predisposition. Asian ethnic groups. In the United States, Hispanics, for example, African American, Asian American, and us Middle Eastern genetic pool, we are all on this. I think there is probably a minority in the world who doesn't belong to this genetic pool. The rest of the world is at a high risk. Patients who already have impaired glucose tolerance or prediabetes before the transplant, of course, are at the highest risk group. And adults with polycystic kidney disease or interstitial nephritis, as well, are in the high risk area. These are non-transplant-induced risk factors. We also have transplant-induced risk factors. For example, medications, and I will touch upon them briefly in the next slide, but organ recipients very often, 100% of the time, require immunosuppressive medications so that the rejection can be prevented. Unfortunately, these medications, corticosteroids, calcineurin inhibitors, and even mTORs can increase the risk of developing post-transplant diabetes. And when you think about it, I have seen this very often to be a problem when I was following pancreas transplant patients. You give a new pancreas to the patient to cure their diabetes, and then you blast them with these high doses of medication that prevents insulin secretion, increase insulin resistance. At the end, they become diabetic again. It's so frustrating to the patient and to us who takes care of them. Not only the drugs, but hepatitis C infection, especially in liver transplant patients, CMV in any solid organ transplant patients, deceased donor allograft, and increased HLA mismatching and some subtypes has been linked to the increased risk of PTDM. And once more, and I have seen this very often during the times that I did transplant clinic in the last 20 years of my career, the post-transplant weight gain has been a huge challenge in the lives of these patients, especially liver disease and kidney disease patients. When you give them a new organ, suddenly they feel better, appetite comes back, and with the help of unfortunate high doses of glucocorticoid, they suddenly gain 30 to 50 pounds that they can, which is around 20 almost kilos. This is just a little, let me see if we can show it, no, let me see if I can show this, no, that's all right. This is just showing you where some of these drugs may affect. For example, decreasing the calcineurins and steroids can decrease insulin secretion, so you cause insulin deficiency with increased insulin resistance in the muscle. That is less production with more requirement that can affect the patient's blood sugar and glucose homeostasis, as well as mTOR inhibitors that also affect better cell proliferation in these patients. So how do we diagnose before we move forward and talk about how are we going to manage? I think it's also important to understand that the first 45 days after the transplant, diagnosing diabetes might not be a good idea. Patients who develop due to the stress and high doses of medications that they are exposed to, they can have transient post-transplant hyperglycemia that needs to be treated. However, diagnosis of permanent diabetes might not be possibly made reliably during that time. This time of vulnerability for our patients continues up to a year after which you can actually very much rely on the result and say that they develop permanent dysglycemia and diabetes. One other tip that I would like to give you is what to use to diagnose PTDM, which is a little bit different than what we do for a normal, regular population. You can still use the random plasma glucose of more than 200 or fasting plasma glucose of more than 126 twice. However, the most reliable diagnosis of the post-transplant diabetes can be done with OGTT, which means that a person can have a normal fasting but still be diabetic. The hemoglobin A1c in this population might not be as reliable as a normal individual. Why? As you know, they might be anemic. They might have hemolysis. They might be recovering from kidney disease and liver cirrhosis after the transplant. Hemoglobin A1c in this population might not be as reliable as we do see in the normal population. The current international consensus on post-transplant diabetes suggests that we screen anyone who is on a waiting list to understand their risk factors so that we could intervene and prevent the progression for the organ they will receive and for the patients themselves for their decreasing mortality and cardiovascular risk. This needs to be done in different times before the transplant. The second suggestion is that right after the transplant, three to four months after the transplant, and a year later. So what are these possible interventions and how do we treat? So we are going to go over the information and the data together. And hopefully I will not bore you to death and I am looking to make sure my watch is on because I will make sure to give the rest of my speakers enough time. Lifestyle changes are extremely important, but the studies that looked into lifestyle changes and prevention of PTDM has not been very successful. We still recommend that we do lifestyle changes. We give the patients nutrition information, however, that alone might not be enough. Also the oral medications, insulin therapy, combination of everything, and bariatric surgery might be some selected options. So let's look at each one of them. So post-op hyperglycemia, right after the patient receives the transplant, which we see a lot in our own hospital in Cleveland, most possibly should be treated with insulin. This has been a classic teaching and the data, even though it lacks necessarily huge benefits, we do know that that is the safest thing to do right after transplant. This is a study that looked at, for example, in South Carolina, the post-operative patients that were assigned to strict IV insulin infusion blood sugar control, less than 100, versus sliding scale or sub-q supplemental insulin. You could see that giving the patient, I wish I could show you, okay, can you see my little pointer? No. Okay. So there, what you see doing worse is actually the strict controlled individuals. So strict control did not perform better than a regular blood sugar control. So from this study, we can just say, yeah, can I use this? Does it work? No, it doesn't work. Or someone is showing me how to do it. Now? Yes. Thank you so much. So they had more hypoglycemia in the intensive treatment group. There was no difference in delayed graft function and not statistically significant, a little bit more rejection in the IV insulin intensive treatment, which does not mean we should not treat them, just means that we have to be just using the same criteria we use for the non-transplanted patient in the hospital setting. And here, this also review is an excellent paper, if you want to read more, by Dr. Cussey and J.C.M., published in January 2024, gives us the tips about what we should do if we are dealing with post-transplant increased blood sugar right after the transplant. And I do use this tremendously. Here I don't, I agree with him 100%. Giving just a supplemental insulin to a patient with very high steroid intake is not a good idea. You could do a once a day basal insulin with some supplemental. However, to be able to bring their morning sugar low enough, you will need such a high levels of long acting that you will cause hypoglycemia at night, so it's not a good idea. These two are my favorites for myself, honestly, in our hospitals, that's what we use a lot. Matching NPH and MPH dose with the steroid, the high dose steroids, and then either using supplemental insulin the rest of the day, or I do combine a basal insulin, supplemental insulin, and an NPH insulin just for the steroid, because that gives me flexibility to lower NPH as the steroids are being tapered down, and it's safety, so the patient won't get hypoglycemic. You could use just basal, which is around 30% of the daily dose, with boluses that will be around 70% of the daily dose, which is different than 50-50 in patients on high steroids. I personally don't like, from my own experience, this model, just because when they decrease the steroids, and patients might not always eat something that increase dose, if they get it, which happens in my hospital often, the nurses will just give the insulin without even waiting a patient eats it or not, then you get into the issue of hypoglycemia. Personally, my favorite one is the NPH with steroids, and then basal insulin and boluses that will not cause hypoglycemia. Then, what do you do once the patients are moving outside the hospital? And here, for decades, we struggled, as we did not have this amazing class of medications that we have today. Metformin can be used, but with caution. The data and each of this group of medications, the information is extremely sparse. It's not a lot that you can for sure, with a confidence, say, this is the truth, but the truth, I trust this, and I will do it to benefit my patients. It's not the case. We just don't have enough information in the literature. Some, metformin seems to be safe. However, I have not used metformin in patients post-transplant, especially kidney patients, just because their clearance and creatinine fluctuates very labile the first four months or so. And I was very much concerned about the possibility of lactic acidosis in my patients. The same for liver transplant. So I would personally avoid metformin until everything is more stable. The safety data, that is the largest data available, is from the United States Pharmaceutical Claims data. How reliable is that data? I would question it. They found that patients with lower creatinine clearance and this and that, high risk, did not use metformin anyway. So you already exclude those individuals that is harmful. So your information about safety only includes people who are safely can use it. So I think if that's what you have and you want to use it, you could. However, be careful with it. DPP-4 inhibitors, I have used DPP-4 inhibitors a lot when they were available first time around 2007 in the United States. They said it was a great group of medication because of their safety. None of their studies proved any cardiovascular benefit in transplant or non-transplant patients. But they are safe. So when I needed something that I can trust that won't cause hypoglycemia, won't do anything to the kidney or liver in cirrhotic patients, when you don't know what else to do, in mild hyperglycemia where you don't want to start insulin yet, for example. That can be used. It's weight neutral, it's safe, it's not my first choice, but it's a good option to have in our toolbox because we need more options than less. As diversity of our patients are there in front of us, we need to have options to choose. The thiazolidinodions, the pioglitazone is the one we have in the United States. I was a fan of this group of medication when they first arrived in the market around 1997. The pioglitazone has information about improving NASH or MASH that I'm gonna talk in couple hours. And it has some information about reducing cardiovascular events. This is not transplant patient, this is regular type two diabetes patients. They can be used, however, especially kidney transplant patients are very prone if you have experience with them to retain water. And you know pioglitazone will promote water retention. Weight gain, some people think that four to five kilo is not much, to me, it is a lot of weight. I don't want my patients to gain anything. However, it's a good insulin sensitizer. If you don't have, you ran out of the options, you need something, it can be used. It has been shown to not affect the immunosuppressive drug level and so forth, which is the safety, so you could. Sulfonylureas, I do not use them due to hypoglycemia risk. What about the great medications that everyone is talking about, can we use them in transplant patients? Glucagon, the GLP-1 agonist, and their cardiovascular outcome is very well known in type two diabetes or people with obesity without type two diabetes. Their renal benefits are well received and we are hoping to get an indication in U.S. And their effect to mash the fatty liver is also well known. So we love this group of medications. And the data is very, not very strong, but we do have some information that they are safe in transplant patients. This is a study that was a retrospective study, pulled 382 patients, matched them with their risk factors. So it was effective in lowering the weight, lowering hemoglobin A1c, improving the lipids. And it was actually, in this study, was linked to decreased MACE in the group that used GLP-1. The study has a lot of flows. However, it was a good information to see. Another study that was more like a meta-analysis looked at the articles that was published in the literature. And in this one, what they were able to show that, I'm sorry. Hemoglobin A1c, good response. Weight loss, good response. No effect to creatinine, great. It didn't make anything worse. Decreased protein in the urine, great. Side effect profile, extremely similar to what we see in non-transplant patient. And the best news ever, no significant change in tachycardia levels, which is very important. When they delay, you delay the gastric emptying, as we saw with terzapatide and birth control pills that we didn't know before that it actually affected the absorption, even if it's transient. So the immunosuppressive drugs, we cannot afford having a change in the levels. And that was a great news. So to me, GLP-1s currently can be used before, during, after transplant, as long as the patients can tolerate it. The SGLT-2s, another group that we have a lot of information about, heart failure readmissions, mortality, kidney disease. So many great benefits to non-transplant patients. Again, not a very strong information in the literature. However, this was from Spain, an observational study, 340 patients. They looked at the side effects of the drug, which I think is the most important in SGLT-2s. I would be extremely worried about urinary tract infection in this population, because they are already taking immunosuppressive drugs. You're dealing with kidney transplant. If you cause pyelonephritis or a fungal infection in the kidney that you just gave, that's a huge disaster. So they did observe that there was loss of body weight, blood pressure improved, A1C improved, all the great things. The risk of developing urinary tract infection was increased in patients who had a history of UTI and in women. So I would be careful and not give it the first four months or so. Wait until everything is stabilized, then give it and try. And if a patient develops UTI, I would probably, I usually have a threshold of two UTIs or of severe yeast infection. I would be careful, more probably careful in this group, just because we don't have room for error with them. Another thing I want you to notice is magnesium. It increases magnesium, which is amazing, because these patients has always very low magnesium levels and we have hard time to improve it. It also improved the protein. This is another one that I will just briefly mention. North, from South Korea, a large retrospective review. They looked at different outcomes and it did have actually all-cause mortality and decreased creatinine doubling together as a composite outcome, not separated outcomes. Terzapatide, I do use it a lot. For patients who cannot tolerate GLP-1s, in my experience, they do tolerate terzapatide, even though it's very similar and has similar side effects. I am so sorry. However, we don't have much information. This is the only information I found in the ADA website. It's not published yet, as far as I can tell, but it seems like not affect the tachrolimus level. It seems to be safe, so we could, I think, use it, if we have to. Liver transplant, very much similar. DPP-4 inhibitor seems to be safer. PIO can be used. SGLT2, you need to be a little bit careful because it is metabolized in the liver and waiting before you start. The same with GLP-1, waiting three to six months before you start. And I will just say bariatric surgery in very much BMI, more than 40 patients can be done before or after. Together with the transplant, seems to be a little bit higher risk in patients' complications. We are currently doing the big data utilization in our hospital system to understand how we can manage the gaps. We do have a developing programs with artificial intelligence to help our providers to give the best care, and with both of them trying to find and individualize ways to help our patients. We have a very robust home care, hospital at home program at the university hospitals. We use CGM in the hospital, even though it's not approved by FDA, and discharge the patients home with it. And we very, very aggressively use telemedicine to follow them up. Thank you so much. Shukran, I believe. Thank you.

post-transplant diabetes mellitus

graft loss

immunosuppressive medications

lifestyle changes

insulin treatment

metformin