Save the date for the following spring dinner meetings:

• March 20th, 2025: Dinner Meeting
• April 17th, 2025: Dinner Meeting
• May 15th, 2025: Dinner Meeting

STLSHP recently started a mentoring program. Students, residents, and senior pharmacists have been paired up to foster relationships among the St. Louis community.

The 2024 Q4 Newsletter “Therapeutic Refill” is out now! Featured articles written by local students are “Sotagliflozin in Heart Failure” and “Unavoidable Drug-Drug Interactions: Transplant Immunosuppression and Antimicrobial Agents”. The Newsletter is posted on our new website. Shout out to our editor in chief Emily Owen for putting this together!

In many patients with end-stage organ failure, transplantation may be a potential option. Transplantation has been associated with an overall improvement in patient outcomes and quality of life. With this comes various risks including post-transplant diabetes mellitus (PTDM). Although as many as 10-40% of post-transplant patients may experience PTDM¹, there is a significant lack of data as compared to other types of diabetes. Most transplant patients are at significant risk for developing PTDM due to tacrolimus and prednisone being key agents in post-transplantation immunosuppressive regimens. Tacrolimus decreases insulin secretion from the pancreas. It also decreases insulin production and glucose transporter type 4 receptors (GLUT4), which decreases glucose uptake into cell². Immunosuppressive regimens often include corticosteroids such as prednisone that cause insulin resistance by altering signaling cascades, mainly GLUT4, resulting in a significant reduction of glucose uptake and glycogen synthesis. These mechanisms result in an additive increased risk of hyperglycemia and PTDM⁴. Currently, PTDM and Type 2 Diabetes Mellitus (T2DM) are treated similarly. However, the difference in etiology suggests that a difference in treatment regimen for PTDM may be warranted.

Most cases of PTDM occur in solid organ transplants, with the highest incidence seen in liver transplant patients with 20-40% of patients being diagnosed. Modifiable risk factors for PTDM include tacrolimus use, obesity, physical activity, smoking, and corticosteroid use⁴. Other pertinent modifiable risk factors include cytomegalovirus infection, hyperlipidemia, and hypertension. Alternative immunosuppressive medications, such as cyclosporine, come with lower risk for patients developing PTDM and may be considered in high-risk patients. Non-modifiable risk factors include age and previous hepatitis C virus infection⁴. In addition to these risk factors, changes within patients' post-transplant immunosuppressive regimens, such as maintaining tacrolimus troughs ≤5.9 ng/mL5, tapering steroids, or using cyclosporine instead of tacrolimus can reduce PTDM risk.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been studied as a potential option for both PTDM treatment and prophylaxis for patients at high risk. GLP-1RAs act by increasing glucose-dependent insulin secretion, slowing gastric emptying, and decreasing unnecessary glucagon secretion³. This class of antidiabetics is highly efficacious in diabetes management, with an average A1C reduction of 1.9%⁶. A study that analyzed cardiovascular outcomes in solid organ transplant patients with T2DM, GLP-1RAs were shown to have the added benefit of cardioprotection. To evaluate the degree of cardioprotection of these agents, the rate of major adverse cardiac events (MACE) including nonfatal cardiac events, ischemic stroke, and all-cause mortality was studied as the primary outcome. The study compared MACE rates in solid organ transplant patients taking GLP-1RAs and those who were not prescribed GLP-1RAs and found that 54% of patients in the control group experienced MACE, with only 21% of patients in the GLP-1 group having experienced MACE (p = 0.004)⁷. In addition to their A1c lowering and cardioprotective benefit, they may be nephroprotective and may also induce weight-loss⁸.

Results in efficacy and safety trials for GLP-1RAs in PTDM have been promising, but data overall is limited. Few studies exist that focus on PTDM. Therefore, data from studies of patients with previously diagnosed T2DM is used to guide recommendations. A study in solid organ transplant patients previously diagnosed with T2DM found no significant change in A1c pre- and post-transplant but did find a notable reduction in insulin use by a median 30 units (p = 0.007)⁸. Similar findings were observed in a retrospective study that observed efficacy and safety of GLP-1RAs in PTDM patients. Overall, there was a significant difference in median A1c from baseline to 3 months to 12 months of 0.8%². In addition to GLP1-RAs impacting A1c, there is growing literature surrounding other outcomes. When compared with safety data from the general population, adverse event rates are significantly lower. A study of patients with PTDM treated with GLP-1RAs reported only 7.1% of patients experiencing hyperglycemic events, 7% with nausea, and 4.2% with pancreatitis². A study found that in non-solid organ transplant patients, nausea and vomiting occurred in 23.4% of patients, pancreatitis in 3.4% of patients, and hypoglycemia in 23% of patients⁹.

Given the positive efficacy and safety outcomes, GLP-1RAs should be considered for initiation in solid organ transplant patients. There is some controversy on whether to start GLP-1RAs prophylactically or upon diagnosis of PTDM. After their first 1-3 months¹¹ post-transplant, it may be a beneficial option to initiate GLP-1RAs prophylactically reduce risk of developing PTDM and to improve cardiovascular and renal outcomes. Other antidiabetics may be considered based on individual patient characteristics and comorbidities. These may include insulin, sodium glucose cotransporter-2 inhibitors, thiazolidinediones, metformin, and dipeptidyl peptidase-4 inhibitors. Although there is minimal data on GLP-1RA use for management of PTDM, current data on the subject show promising results, suggesting potential changes to PTDM treatment guidelines.

References
1. Chowdhury TA. Post-transplant diabetes mellitus. Clin Med (Lond). 2019;19(5):392-395.
2. Sweiss H, Hall R, Zeilmann D, et al. Single-center Evaluation of Safety & Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Solid Organ Transplantation. Prog Transplant. 2022;32(4):357-362.
3. Perez A, Jansen-Chaparro S, Saigi I, Bernal-Lopez MR, Miñambres I, Gomez-Huelgas R. Glucocorticoid-induced hyperglycemia. J Diabetes. 2014;6(1):9-20. doi:10.1111/1753-0407.12090
4. Wang R, Zhang Y, Fan J, Wang Z, Liu Y. Risk Factors for New-Onset Diabetes Mellitus After Heart Transplantation: A Nomogram Approach. Transplant Proc. 2022;54(3):762-768.
5. Song JL, Li M, Yan LN, Yang JY, Yang J, Jiang L. Higher tacrolimus blood concentration is related to increased risk of post-transplantation diabetes mellitus after living donor liver transplantation. Int J Surg. 2018;51:17-23.
6. Liou JH, Liu YM, Chen CH. Management of Diabetes Mellitus With Glucagonlike Peptide-1 Agonist Liraglutide in Renal Transplant Recipients: A Retrospective Study. Transplant Proc. 2018;50(8):2502-2505.
7. Dotan I, Rudman Y, Turjeman A, et al. Glucagon-like Peptide 1 Receptor Agonists and Cardiovascular Outcomes in Solid Organ Transplant Recipients With Diabetes Mellitus. Transplantation. 2024;108(7):e121-e128.
8. Kukla A, Hill J, Merzkani M, Bentall A, Lorenz EC, Park WD, D'Costa M, Kudva YC, Stegall MD, Shah P. The Use of GLP1R Agonists for the Treatment of Type 2 Diabetes in Kidney Transplant Recipients. Transplant Direct. 2020 Jan 13;6(2):e524.
9. Aldhaleei WA, Abegaz TM, Bhagavathula AS. Glucagon-like Peptide-1 Receptor Agonists Associated Gastrointestinal Adverse Events: A Cross-Sectional Analysis of the National Institutes of Health All of Us Cohort. Pharmaceuticals (Basel). 2024;17(2):199. Published 2024 Feb 2.
10. Moes DJ, Press RR, Ackaert O, et al. Exploring genetic and non-genetic risk factors for delayed transplantation function, acute and subclinical rejection in renal transplant recipients. Br J Clin Pharmacol. 2016;82(1):227-237.
11. Pham PT, Sarkar M, Pham PM, Pham PC. Diabetes Mellitus After Solid Organ Transplantation. In: Feingold KR, Anawalt B, Blackman MR, et al., eds. Endotext. South Dartmouth (MA): MDText.com, Inc.; July 13, 2022.