Introduction
Diabetes mellitus (DM) in kidney transplant recipients (KTR) significantly increases the risk of mortality, infections, and long-term graft loss. Early identification and prevention strategies, especially for patients on the transplant waiting list, can help reduce the incidence of post-transplant diabetes mellitus (PTDM). Adjusting immunosuppressive therapy may also improve glucose control. Recently, newer antidiabetic drugs like GLP-1 receptor agonists, SGLT2 inhibitors, and finerenone have shown cardiovascular and renal benefits, prompting their increasing use in transplant recipients, despite limited data in this population.
PTDM remains a common complication post-transplant, with a reported incidence of 24% within three years. It results from a combination of traditional type 2 DM risk factors and transplant-specific factors like immunosuppressants, hypomagnesemia, and infections. Early detection using tests like OGTT can guide timely interventions to delay or prevent diabetes progression. While insulin is still the primary treatment, the emerging use of newer glucose-lowering agents offers potential for better renal and cardiac outcomes, though more transplant-specific research is needed to define optimal treatment protocols.
Risk Factors for Diabetes Mellitus Post Transplant
The development of diabetes mellitus after kidney transplantation is influenced by both traditional risk factors—such as obesity, metabolic syndrome, older age, male gender, and family history—and transplant-specific factors. Hepatitis C infection and genetic predispositions like certain interleukin gene polymorphisms also increase the risk. In transplant recipients, the use of immunosuppressive drugs like corticosteroids, calcineurin inhibitors, and mTOR inhibitors plays a major role in impairing pancreatic beta cell function and promoting insulin resistance.
Corticosteroid dose, especially ≥10 mg/day of prednisone, is linked to increased insulin resistance, although reducing the dose to 5 mg improves insulin sensitivity to some extent. However, complete withdrawal offers no additional benefit. Tools like indirect insulin resistance indices can help predict PTDM risk. Notably, while tacrolimus reduces rejection and graft loss, it also increases the incidence of insulin-dependent diabetes, highlighting the need for a careful balance in immunosuppressive management.
Impact on Cardiovascular Health
Patients with diabetes mellitus (DM), especially type 2 DM, face a significantly higher risk of cardiovascular complications such as coronary heart disease, stroke, heart failure, and peripheral arterial disease. Additionally, DM is a leading cause of chronic kidney disease (CKD), which further increases cardiovascular risk. Albuminuria, in particular, is a strong independent predictor of kidney failure and cardiovascular events, highlighting the need for regular screening for both CKD and cardiovascular disease in diabetic patients.
In kidney transplant recipients (KTRs), cardiovascular disease remains the leading cause of death, accounting for over half of post-transplant mortality. This increased risk stems from a combination of pre-existing atherogenic factors, transplant-related risks like post-transplant diabetes mellitus (PTDM), graft rejection, and long-term effects of immunosuppressive therapy. PTDM significantly contributes to cardiovascular complications and mortality, making early risk assessment essential. The oral glucose tolerance test is the preferred method to detect PTDM and initiate timely interventions to reduce associated risks.
Complications and Long-Term Consequences of DM in KTR
Patients with type 2 diabetes (T2DM) are often older and have multiple comorbidities, which reduces their chances of being listed for kidney transplantation. Studies like the Finnish registry report a lower probability of transplantation in diabetic patients compared to non-diabetics. Survival rates post-transplant are generally lower in diabetic recipients, though death-censored graft survival appears similar. Data from Australia also indicate higher early mortality in diabetic kidney transplant recipients (KTR), especially in younger patients.
However, recent studies show improved outcomes, with 5-year survival in diabetic and non-diabetic KTRs now approaching similar levels. PTDM (post-transplant diabetes mellitus) is linked to higher risks of infection, graft loss, and mortality. A meta-analysis reported a 67% higher all-cause mortality and 35% higher graft loss in PTDM patients. Yet, some studies suggest PTDM may not significantly affect survival, whereas pre-transplant diabetes shows a stronger link with increased mortality risk.
New Pharmacological Interventions in KTR
Sodium Glucose Cotransporter-2 Inhibitors
In T2DM patients, adding SGLT2 inhibitors (SGLT2i) and GLP-1 receptor agonists (GLP-1RA) to standard therapies (like antihypertensives, statins, and antithrombotics) is recommended to lower cardiovascular risk, regardless of blood sugar control. In those with CKD, finerenone (alongside ACE inhibitors or ARBs) is also advised to reduce cardiovascular and kidney failure risks. While these drugs have shown strong benefits in non-transplant populations, data in transplant patients remain limited.
SGLT2i work by promoting glucose and sodium excretion in urine, improving kidney function and reducing filtration pressure, thus protecting against kidney damage. Though evidence from randomized trials shows significant cardiorenal benefits in the general population, transplant-specific data are sparse. A small study in PTDM patients post-transplant showed improved glucose control and weight loss without adverse effects. Larger studies, including a Spanish multicenter study, reported a 10.3% UTI rate with risk factors like female gender and prior UTIs. Early findings suggest SGLT2i may also reduce cardiovascular events in transplant recipients, and more clinical trials are currently underway.
Glucagon-like Peptide Receptor Agonists
GLP-1 receptor agonists (GLP-1RAs) work by mimicking incretin hormones, which boost insulin secretion after meals. These drugs help improve blood sugar control, reduce weight, lower cardiovascular risk, and enhance survival in T2DM patients. Studies like SUSTAIN 6, LEADER, and FLOW have shown reduced kidney disease progression, lower albuminuria, and fewer cardiovascular events with semaglutide and liraglutide.
Although transplant recipients (KTR) were excluded from major trials, smaller studies and reviews suggest GLP-1RAs are effective and safe in KTR—improving glycemic control and weight without affecting immunosuppressive drug levels or eGFR. Semaglutide also aids weight loss in dialysis patients, helping obese patients qualify for transplant surgery. Moreover, GLP-1RAs may protect beta cells from damage caused by immunosuppressants. Ongoing trials are evaluating their broader role in DM and obesity management post-transplant.
Finerenone
Finerenone is a selective non-steroidal mineralocorticoid receptor antagonist (MRA) with fewer side effects (e.g., gynecomastia, hyperkalemia) compared to steroidal MRAs. It reduces inflammation and fibrosis in kidney tissues, leading to lower albuminuria and slower CKD progression.
Clinical trials (FIDELIO-DKD & FIGARO-DKD) showed finerenone lowers the risk of renal failure and cardiovascular events in T2DM patients with CKD already on ACE-i or ARBs. It’s recommended for patients with eGFR >25 mL/min/1.73 m² and UACR ≥2 mg/g, with potassium monitoring.
Kidney transplant recipients (KTR) were excluded from trials due to drug interactions (both finerenone and tacrolimus are metabolized via CYP3A4). A Phase II trial is ongoing to assess its safety and efficacy in KTR.
Conclusion
Emerging therapies in T2DM, such as SGLT2 inhibitors and GLP-1 receptor agonists, offer promising kidney and cardiovascular protection and are increasingly used in kidney transplant recipients (KTRs), despite limited guideline inclusion. These agents show benefits in metabolic control and proteinuria, with manageable side effects, and may aid obese patients awaiting transplantation. Novel treatments like dual/triple receptor agonists (e.g., tirzepatide) and new insulin analogs are under development but remain untested in KTRs. Finerenone, although effective in T2DM with CKD, has potential drug interactions with tacrolimus, making its use in transplant settings complex and dependent on ongoing trials like EFFEKTOR. While SGLT2i and GLP-1RA appear safe and effective in KTRs, more evidence is needed to confirm long-term cardiovascular and mortality outcomes, potentially influencing future transplant guidelines.
References
1. González Delgado, A.; Hernández, A.F.; Marrero, D.; Maside, A.F.; Barroso, G.H.; Carreño, E.P.; Acosta Sørensen, C.; Rodríguez-Rodríguez, A.E.; Collantes, T.; Anabel, R.; et al. Inflammation on the Waiting List Is a Risk Factor for New-Onset Prediabetes and Post-Transplant Diabetes Mellitus: A Prospective Study. Nephron 2023, 147, 560–571.
2. Sharif, A.; Hecking, M.; de Vries, A.P.J.; Porrini, E.; Hornum, M.; Rasoul-Rockenschaub, S.; Berlakovich, G.; Krebs, M.; Kautzky-Willer, A.; Schernthaner, G.; et al. Proceedings from an international consensus meeting on posttransplantation diabetes mellitus: Recommendations and future directions. Am. J. Transplant. 2014, 14, 1992–2000.
3. Sharif, A.; Chakkera, H.; de Vries, A.P.J.; Eller, K.; Guthoff, M.; Haller, M.C.; Hornum, M.; Nordheim, E.; Kautzky-Willer, A.; Krebs, M.; et al. International consensus on post-transplantation diabetes mellitus. Nephrol. Dial. Transplant. 2024, 39, 531–549.
4. Torres Ramírez, A.; Rodríguez Rodríguez, A.E.; Porrini, E. Diabetes Tras el Trasplante Renal; Lorenzo, V., López Gómez, J.M., Eds.; Nefrología al día; Elsevier: Amsterdam, The Netherlands, 2023; ISSN 2659-2606.
5. Jenssen, T.; Hartmann, A. Post-transplant diabetes mellitus in patients with solid organ transplants. Nat. Rev. Endocrinol. 2019, 15, 172–188.
6. Zhu, K.; Qian, F.; Lu, Q.; Li, R.; Qiu, Z.; Li, L.; Li, R.; Yu, H.; Deng, Y.; Yang, K.; et al. Modifiable Lifestyle Factors, Genetic Risk, and Incident Peripheral Artery Disease Among Individuals with Type 2 Diabetes: A Prospective Study. Diabetes Care 2024, 47, 435–443.
7. Zoulakis, M.; Johansson, L.; Litsne, H.; Axelsson, K.; Lorentzon, M. Type 2 Diabetes and Fracture Risk in Older Women. JAMA Netw. Open 2024, 7, e2425106.
8. Chen, S.; Bowen, D.G.; Liu, K.; Vidot, H. Hypomagnesaemia, an independent risk factor for the development of post-transplant diabetes mellitus in liver and renal transplant recipients? A systematic review. J. Hum. Nutr. Diet. 2024, 37, 1407–1419.
9. Wang, X.; Chen, J.; Cao, Z.; Yu, X. Associations between human cytomegalovirus infection and type 2 diabetes mellitus: A systematic review and meta-analysis. BMJ Open 2023, 13, e071934.
10. Torres, A.; Hernández, D.; Moreso, F.; Serón, D.; Burgos, M.D.; Pallardó, L.M.; Kanter, J.; Díaz Corte, C.; Rodríguez, M.; Diaz, J.M.; et al. Randomized Controlled Trial Assessing the Impact of Tacrolimus Versus Cyclosporine on the Incidence of Posttransplant Diabetes Mellitus. Kidney Int. Rep. 2018, 3, 1304–1315.
