Shumei Meng, MBBS, PhD, provides a review of post-transplant Diabetes Mellitus and explains the Transplant Endocrine Program at The Ohio State University Wexner Medical Center.
thanks. Thank you for this opportunity to share with you about post transplant diabetes and to review our transplant into Quinn program at OS you. We all know that Ohio State is the home to Central Ohio's only adult transplant center that has caring for patients with transplant off the heart, lung, kidney, liver and pancreas. We probably still recall the excitement we had when we celebrated our 10,000 transplant milestones at OS you last August. Nationally, we're ranked at number 10 by volume. With the increased number off a transplant. The Inter Quinn care in transplant has become a bigger challenge, but also a greater opportunity. This achievement is built upon a multidisciplinary team. As an endocrinologist, I'm honored to be part of the team today. I would like to give you a review off the post transplant diabetes and the introduction off our unique transplant in the Queen program. My objectives, including three number one. We're going to review the risk factors, prevalence and impact off post transplant diabetes. Then we're going to review the most up to date management off post transplant diabetes and the challenge we face. Lastly, I will give you the introduction off the transplanted A Queen program and share with you our experience off the establishment off this unique program. First of all, for all, let's look at the case. Ah, 50 year old patient had a living donor renal transplant two weeks ago. He has been on cyclosporin and micro finale for immune suppression. His renal function is normal, but his glucose has been elevated in a 200 mg per desk later persistently on his labs. What is the best initial therapy? Should we start using first? Should we do GOP one the good cooking like peptide one. Should we use made for me? Or should we start? S g o T two inhibitor. So Demag local School Transporter two inhibitor. Welcome to that case in the end, so as many people is familiar with this slide, this is the most recently updated Type two diabetes management guidelines from American Diabetes Association. And like the Type two diabetes, there is no solid guideline in the post transplant diabetes management. So far, post transplant diabetes refers to diabetes that develop post transplant. It's used to called No debt was trying to define more accurately as diabetes that develops post transplant in previously no diabetic patients, however critically. This is very hard to determine, as a matter of fact, since last published the International Consistence guideline in 2003. So far, there is only one up. Great update on this area is a published the proceedings from an international consensus meeting in 2014. According to this new proceedings, the diagnosis of a post transplant diabetes is a pretty much consistent with diabetes diagnosis criteria from a d. A. You can diagnosis the patient based on two positive finance from those several criteria. It can be a fasting plasma glucose, more than or equal to 1 26 mg per death. Later, it can depend on random locals more than or equal 200 mg Podesta later, in addition to symptoms off a poly real politics CEO are expected with loss. It also can use a two hour post post 75 g o g t t value, off 200 mg per desk later Ohio. You could incorporate the event see value off more than 6.5%. However, due to the commonly and the estimated severity of diabetes with even see in post transplant patients is recommended do not start to consider MNC as a main criteria until three months. Post transplant The risk factors for post transplant diabetes is share a lot of common risk factors like Type two diabetes, for example, H b M i. Research or politics of family history. However, it also has a lot off unique risk factors related to the transplant, such as the politest, kidney disease, seeing the renal transplant or cystic fibrosis, you long transplant and many factors. Associative is inflammatory disease, such as hepatitis C, C M we infection or H L. A mismatch. Mostly importantly, many immune suppressants has been shown to be associated with increased risk for post transplant diabetes. This slide show you many immune suppressant directly interact. Interact with insulin, signaling pathway through a very specific steps among the insulin signaling pathway to cause increased risk off a post transplant diabetes. In general, critical steroid is causing mainly insulin resistant, but it may also cause better cell dysfunction. Cassie New inhibitors such as cyclosporin or Takla llamas. It mainly cause impaired insulin secretion but also can cause insulin resistance. Similar M Tory inhibitors and it can cause mainly through insulin resistance, but also has some impaired insolence. Christian There's a few other immune suppressants such as the actual Siberian or micro family, or, better to accept has not been showing to be diverted genic so far. How often we see post transplant diabetes in the transplant recipients. This study was published in 2001 by our own transplant center is this graph shows the patient, transplanted prior to 1994 had showed about 6% off the post transplant diabetes at six months after transplant. However, in a patient transplanted after 1995 has significantly higher incidence of a post transplant. Diabetes is almost Dabord, and from this slide, you can tell there's a clearly the patient transplanted after 1995 is significantly higher age and the increased weight. So now you may answer the question with people generally getting heavier and transplanted later. So what's the current incidents? It turned out there is no consensus data on this information depend on the study. What kind of a diagnosis criteria they used for the diagnosis, but also what kind of patient selection used for the transplant population. So that reported the incidents has been various ah lot, not just the data published years ago but given the recent ones, has showed large variation on the incidents. For example, renal transplant recipient has shown the instance off. Post transplant diabetes is about 9 to 18% and the liver transplant has about 20 to 30% reported, and in the heart transplant it can be around 29% and the long transplant is about 26 to 40%. Why do we care about post transplant diabetes? Compared to non diabetes transplant recipient? The patient with post transplant diabetes have a significantly decrease survival rate. Not surprisingly, the pre existing diabetes transplant patient have even lower survival rate. The read off free off a cardiac event compared to non diabetic patient. The recipient with new answer Post transplant diabetes is much lower off course. The pre existing diabetic transplant recipient has lowest free of a cardiac event, so this slide show your post transplant diabetes is correlated with much higher cardiovascular mortality. Off course the patient have preexisting diabetes has even higher reach about 39% of a cardiovascular mortality since, as I mentioned earlier, I like the frequently updated Type two diabetes management guidelines from a D. A there is no clear guidelines for post transplant diabetes, then the question is. What's the difference between post transplant diabetes and type two diabetes? Ah, common theory it described on this slide Immune suppressant and many other stressors can lead to the transit impairment off insulin secretion. However, if insulin therapy or lifestyle are applied earlier on to this transplant patient to achieve optimal glucose control, beta cell may be protected. Then the useless security maybe can be maintained. So what's the data to support? That there is a small clinical trial was studied in 50 renal transplant without previous hitch of diabetes on tech llamas. They were randomly assigned to two groups. One is the treatment group in this group, pushed actively started daily morning nph insulin. If blood glucose is more than 11 40 mg per desk later on the previous evening record and the second group is a control group, they're placed on standard of care and you use Orel anti diabetic agent. If glucose is more than 80 and if it is more than 2 50 is considered short acting insulin to use correcting the hyperglycemia. So the treatment groups, specifically en Ph 68 or 10 unit was initiated for black locals off 1 41 80 or 2 40 mg. But that's that's later respectively. And the dose was tight, treated to a target glucose of 1 10 to 1 20 mg Padesh later, further correction was made with sliding scale insulin. The standard of care group was maintained by the primary care physician. They usually don't recommend treatment when the glucose is less than 1 80 mg per desk. Later, a softening your area, which is not available in US called Jelly Closet, is available at the Europe was suggested as the agent of a choice. If Glaucus was over 2 50 mg per desolate er, despite this Orel agent sliding scale of insulin was applied to correct for the hyperglycemia. Interestingly, you can tell by three months on the therapy or control. The patient on the diabetes medication has completely flipped. So in other words, after three months, there's very few patients remain on diabetes treatment. If they were initiated in Ph earlier, on and under control group on the other side, the patient remain on diabetes. Medication has shown at much higher numbers from this data. It's illustrated that earlier initiation off the insulin therapy toe achieve optimal glucose control might have decreased in incidents with post transplant diabetes. It might protected the better cell function in the post transplant patient in the long term. Based on this data, this is 2014. Proceedings recommended that earlier incident therapy to treat target control of glucose immediately after transplant might decrease the projected the incidents off post diabetes in the long run. So the further recommended in the beginning first after the transplant in the first seven days to one week in the first seven days. Insulin is the op optimal treatment choice, but from eight days to 45 days, explain is preferred. But other Orel diabetes medication can be considered further down the road 40 sixties to longer term. The typical type two diabetes can be considered, however, what is the typical Type two diabetes regiment? According to the most recent guideline from a D for Type two diabetes, you can tell there's many high risk populations such as CKD, patient or patient. Only have a cardiovascular disease or high risk for cardiovascular disease. GOP one actually is preferred as a first line therapy. It's G O. T. to also has been proposed. So what is the increasing rule in the post transplant diabetes management? As a matter of fact, that has been proposed a while ago in creating should be considered in the management off a post transplant diabetes. Why? For several reasons, Number one in creating is called to react with immune suppressant induced disruption off instance Christian Useless. Also decrease. I'm sorry. Increasing also decreased local guide levels and improve all insulin resistance. The weight loss effect off increasing culture reacts the weight gain commonly seen after transplant. Well, what's the data? There are a little bit data in a basic research tech llamas induced pancreatic alley dysfunction. It can lead to defect. Active GOP one secretion treatment treatment with the MQ 0626 is a D D. P for inhibitor can attenuate tech llamas induced pancreatic ali dysfunction and it caused I laid the morphological changes. The MQ 0626 treatment can rewards the GOP one execution defect induced by tech llamas through the inhibition for apoptosis off the better sell on the reduction for Occidental Stress Direct administration off exceeding four, which is a GOP one toe. Actually, the islet cells can reduce tech llamas, induced cell death and oxidative stress. What's the human data? There's very little data in the clinical research. There is a case. Siri's off five kidney transplant patients on tech llamas who were treated with a lyrical tied for 21 days. It basically showed lyrical tide was pretty safe in these five patients. Later on, in 2018, there was another study with the little girl. Tied was tried in seven renal transplant recipient. It should. Lyrical tide was safe and effective for renal transplant recipient with the pro diabetes control. 18 Hour has been using GOP when you might post transplant diabetes clinic for managing the diabetes patient. So I'm going to show you our data in our clinic. Based on the clinical practice, this is a retrospective. Try to reveal data off our solid organ transplant recipient with diabetes who are treated with the doula. Grow tired from October 30th, 2014 to January 1st 2018 and the S. U. The transplant center. Our aim was to analyze the efficacy and safety off do legally tied in the management off a post transplant diabetes as well as the diabetes in a solid organ transplant. The inclusion criteria, including age over 18 and history off a solid organ transplant and has been on gluten gluten do a glow tied for over six months or longer. Exclusion criteria, including any history of a measure, authority, cancer or history of Pancrate. Hardest Emmy and to family history or severe G I disease. The total 80 receiving were identified. Among them, 63 were included. 43 have a pre existing diabetes, whereas 40 20 patients have a post transplant diabetes. The baseline data were collected at 6, 12, 24 months. The primary and point was changing weight. B M I usually requirements and cardiovascular mobility and graft, survival and all cause mortality, safety and point, including severe and non severe hyperglycemia. G i side effects Pancrate hardest. Goldstone and the new diagnosis off malignancy secondary any point with the agency and renal function. This is a baseline characteristic off the study population. This is very consistent with our typical transplant patient. The media age is 58. The male is about 68%. The risk distribution is very consistent with our common transplant recipient organ transplant, mainly including the patient on kidney transplant, about 81% off the patient, and the 65% off the patient has family. Huge off type two diabetes. A B M I medium read is about 32.5. The crane in level medium is about 1.55 Most patient on immunities Immune suppression. 81% of our own case in your inhibitors, 57% are sale cycle Reince Hey bitters and 54% on amateur inhibitor. There are about 21% on the low dose maintenance steroid, and the 22% has been used higher those steroid for rejection for short time period. The time since transplant Median time is about four years, 47.8 months and the onset of a post transplant patients, most of them, are occurring in the earlier time. After post transplant, there's kidney function. Most of them are in the CKD to to see Katie for orange, and it crossed the border from the different stage and history off the C V D. Before the G O. P. One was used is about 33%. This is consistent the higher mobility off the post transplant patient. This is the outcome off our data. The 6, 12 and 24 months patient has been on doula glow tied. The be my body weight and they're even see, has showed significantly improved except the MNC at 24 months. It did not continue. Go down further. One reason for that could be because we treat the MNC toe a target value off less than 7% once it reached to that value. We do not keep pushing the medication for the driven, the even see down, but we would rather lower the insulin levels. The Jeff the creating level Jeff are, and so I will read, also remained stable. But insulin those has significantly decreased over time. The mortality off the patient and the cardiovascular mobility has remained very safe, very lower it compared. Compared to the typical transplant patient, this is much lower it So in conclusion, two local low tide. It's safe to treat diabetes in solid organ transplant. In selected the patient and the monetary do like a low tide, is effective to treat diabetes, including the post transplant diabetes in solid organ transplant and effective, and it is the effect is actually very sustainable, sustainable. We further compared our patient on do a glow tied with lyrical tied on the management off diabetes in our transplant patient. It demonstrated that both has sustained reduction in wheat B m I usually requirement and even see as well as both exhibited fear a ble side effect profile without interference with immune suppressant. If you look the data specifically the dollar crow tide seems like have a slightly more favorable impact on the wheat as well as even see control. But generally speaking, both have a very stable safety profile. So the question we come to ask how GOP one works well in the post transplant diabetes. Recently, there's a people has published. It might shed some light on this, um, mechanism. How GOP one works in the post transplant diabetes. So here this study tackle llamas and the Sarah Lima's has showed clearly induced human better sale dysfunction. As the 15 minutes off arginine stimulation both tech llamas and the Sarah Llamas caused significantly increased the blood glucose production and the human useless situations is significant decrease already in the base basal level in the tech llamas treated group, but more so in the 15 minutes stimulated the level in both tech llamas and the Sarah Llamas treatment. They use Lin to glucose ratio significantly decreased in the tech Llamas group, you know, at baseline. But at 15 minutes, stimulation both tech llamas and sorrow. Llamas completely decreased the insulin to glucose ratio, suggesting the post transplant diabetes the mechanism off that is probably Mosul off insulin secretion impairment than insulin resistance. Further evidence showed the tackle, LIMAs and Sarah Llamas can cause Emma Lloyd deposition and the Houston Grandeur Information disruption in the tech llamas and Sarah Llamas treatment. And, it turned out, if you withdraw the take llamas or Sarah Llamas for four weeks, this dysfunction is reversible, at least is a partially restored, and similarly, the amyloid disposition is also improved significantly with the withdraw. So treatment is GOP one exceeding four. As you can tell from this last to, uh, picture the exceeding for price tech llamas. Compared to Tech Llamas Group as well as the seller llamas, plus exceeding for compared to the Sarah Llamas Group, the glucose value has been significantly improved as well as the ratio off insulin to glucose ratio. So this data suggest this data suggests the post transplant diabetes. The main mechanism probably is involves the insulin secretion defect. So what is about another new diabetes regiment S G O T. To it Turned out, there's not a whole lot data in this area. There is one study published in 2019, treated with Emma Glow Flushing the S G O. T. Two in renal transplant patients, 22 patient on the treatment, compared to 22 patients on the place. Able it should significant benefits with weight reduction, but there's no significant difference in the GF Are or their immune suppressant drug levels. Similar findings was also found with any empirical frozen in the heart transplant recipient, you can tell there, um, we'd be m. I has significantly improved. Even she was decreased and the even frost might dosage was decreased. But the GF are the cranial level has no difference. Back to the 2000 and 14 international consensus guideline. They recommended the day uh, after the transplant up to seventies insulin is a preferred regiment, and after that, the first week to 45 days you can consider aiding Orel diabetes agent, but the long term they recommend, just go along with the typical push. Typical Type two diabetes measurement, I would add, based on our data and others data the long term therapy for post transplant diabetes. We can continue use lifestyle modification, but newer diabetes agents such as GLP one and even some selected patient with S g o T. Two can be considered off course. Additional typical Type two diabetes agents still can be used as a matter of fact in the practice. Clinically in the post transplant in the Queen Clinic, I have been using almost all of them, but it depends on the inter reaction. With immune suppression and the culpability and the country indication from other organ dysfunction, you had to be individualizing the therapy and the two principles keep in mind. One is to avoid country indication. And in the reaction, when is that considered additional benefit with the diabetes medication? So now go back to our case. This 50 year old gentleman has had a living donor transplant Two weeks ago. He has been on circle. It's pouring and microfinance late for immune suppression. His renal function has bean normal, but his glucose has been elevated persistently in the 200 on his labs. So what is the best? First initial therapy number one starts usually number to start. GOP one number three Statement for me Number four is start S G O T. To my answer will be starting insulin because this patient just heads the recent transplant two weeks ago. Based on the limited data initiated in with useless earlier on toe, achieve optimal glucose control may have a long term benefit to preventing, um, the post transplant diabetes. So this kid's continue. The same patient has been on multiple daily injections for insulin. Now for three months, he required actually a large amount of insulin every day. He has been trying to lose weight, but he said that despite his persistent lifestyle changes, it has not been able to lose in a weight he said even see on the visit today is 8%. So he ask you what he can do. So what is the best next step at this point? Number one is to continue insulin. We can appetite treating the dose. Number two is start GOP one number three. We can do a mat forming because metformin has been should have some weight loss and also his cleaning level has been normal. Number four, we can start self Nuria. So based on our limited data or actually our clinical data, I would start him on GOP one because, like we mentioned earlier, the GLP one has should have very safe profile in our transplant patient. The in impact on the weed control and eventually control has been very good May for me. Long term. Some patient you might consider. But with the patient just had to transplant three months. You don't know this screening level will remain this good level. Yet for long term, we're probably going to be cautious. So with that, I will choose start GOP one for this patient with the post transplant diabetes management. Despite we has accumulated some data that is very helpful to help with the post transplant diabetes, there are many challenges still with face. The main challenge we face right now is Number one is lack off a practical, sensitive diagnostic tools because the fasting glucose is often not impaired in the early stage and the the transplant patient O G TT is not easy to perform and then often is not consistent, even see, value is not very sensitive in the post transplant patient, as we mentioned earlier, mainly due to the higher prevalence of anemia is often and estimate the severity off the diabetes. Another challenge we face is the lack off data on the relationship between the glass EMEA control in the micro macro vascular complications as well as the graft patient survival with the new diabetes agent, even though we've been using clinically see a good information. But we are lacking off big clinical trial to prove that number three is. Can we delay or prevent post transplant diabetes toe quote Martin Luther King Junior's. We must accept finite disappointment but have never lose infinite hope. I hope we continue work on this field to eventually have a better regiment developed to treat this post transplant diabetes. With that, I'm going to switch the gear to introduce you. The post transplant. The transplanted A Queen program as early as 2013 is Dr Ringo has mentioned our leadership from our transplant center as well as our you knew. Quinn Division has come to a common big vision and wanted to work on to build this unique transplant in the Queen program. Since 2013. We have been working from the very beginning to now this this program has become a very comprehensive India Quinn program. As I mentioned earlier with more patient volume, there's a more need for this field. Currently, this integrate program has treating all kind off indicate disease. Most commonly type two diabetes Harpal, epidemiologic and also including Type one diabetes. Bun metabolism disorder are supposes followed and many other into quint disease. The patient number has been increasing over time in this clinic, and also the EU generated in this practice has growing continuously. The revenue we generated from this program has continued to rise despite the coup. In 19 comes we still using many different format off virtual visit and many other ways to continue. So our patient, the patient reserves in this program is very unique because this is a patient, have very high age. You can tell many people, is over age 65 and they are much seek a patient, have a higher com abilities. The area reserves, including the whole Ohio area, but also including the surrounding state such as Indianapolis, Illinois, North Virginia, West Virginia, Chicago can target the all surrounding Pennsylvania Rania. So with this growing program and I would like to ask people to help continue support this program to give us more collaborations so we can work together three directions I want to further work on in the future. Clinically, we're going to transition our transplant, integrate care from more chronic long term care towards urgent care at this point, because our transplant volume has increased in significantly. In order to do that, we need to shift a lot of our stable chronic patient to their local community, provided to assume the care this will create create a big need for the more education in this field. And we need a providing more clear guidelines in the treatment or this field. So number two, we're going to actively conduct future research in this field to provide a better evidence supported guidelines for our general providers in the management off the post transplant diabetes number three, we will increase collaborations with many other subspecialties inside and outside off our transplant center as well as outside the U. S. You. So we're going to collaborate more to the growth and the development off our CTC program. With that, I would like to give thanks to Dr Washburn at a person mento as well as the whole CTC, the team, the faculty staff for their endless support with that, without their support, this program cannot go to today. And also, I would like to thank Dr Ringo and our India Quinn care team for their encouragement and belief. You, me all the time. And I also gave the special thanks to doctor saying and Maria and the Debbie for the the effort they have with me in the collaboration in the research and the clinical practice. And with all that, thanks for everybody. So I think she may. That's a wonderful example of, uh, you know what? We could do A here in Ohio state with really unique novel programs, growing them, building them and then using that Teoh lead Thio data, uh, that air moving the field forward, I think that the impact of the GLP one your understanding just a little bit because I think it really is gonna be a big deal on this has been a big deal for these patients to be able to expand the use of these new diabetes agents that really are transforming in type two diabetes to this, uh, growing population of patients that have had, you know, solid tumor transplant. So thank you very much. That was really terrific.
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