|
1
|
Gordon R, Kerr J, Feist A, Mariski M, Kozuch J. Glucagon-Like Peptide-1 Receptor Agonists Compared to Insulin for Post-Transplant Diabetes Mellitus After Solid Organ Transplant. Transplant Proc 2025; 57:683-687. [PMID: 40140314 DOI: 10.1016/j.transproceed.2025.02.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/24/2025] [Indexed: 03/28/2025]
Abstract
Pre-existing diabetes mellitus (DM) prior to solid organ transplant (SOT) and development of post-transplant diabetes mellitus (PTDM) is common. The use of novel agents, such as glucagon-like peptide-1 receptor agonists (GLP-1 RA), has increased in the general population due to beneficial effects on cardiovascular disease (CVD) and weight loss. However, there is limited data in the SOT population. A retrospective, observational, matched cohort study in outpatient SOT recipients on injectable diabetes therapy was performed at a single academic medical center. The purpose of the study was to compare glycemic control in SOT recipients using a GLP-1-RA-containing regimen compared with insulin-only when initiated within 12 months of transplant. Seventy patients were included in the analysis with 51% of subjects in each group reaching their A1c goal within 1 year after starting diabetes therapy. The median A1c was 7.0% in the GLP-1 RA group and 6.9% in the insulin only group (P = .30). One year after starting diabetes therapy, insulin use decreased to 69% in the GLP-1 RA group, while 94% of subjects in the insulin only group remained on insulin (P = .007). There were 7.2 fewer injections per week in the GLP-1 RA group compared to 4.6 more in the insulin group (P < 0.001). In SOT recipients within 12 months of transplant, the use of GLP-1 RA for blood glucose management had the same A1C goal attainment as insulin-only while allowing for fewer injections per week.
Collapse
Affiliation(s)
- Rachael Gordon
- Department of Clinical Pharmacy, University of California, San Francisco, California.
| | - Janice Kerr
- Department of Pharmacy, University of California, San Diego Health, San Diego, California
| | - Ashley Feist
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, California
| | - Mark Mariski
- Department of Pharmacy, University of California, San Diego Health, San Diego, California
| | - Jade Kozuch
- Department of Pharmacy, University of California, San Diego Health, San Diego, California
| |
Collapse
|
|
2
|
Faruque L, Yau K, Cherney DZI. Glucagon-like peptide-1 receptor agonists to improve cardiorenal outcomes: data from FLOW and beyond. Curr Opin Nephrol Hypertens 2025; 34:232-240. [PMID: 40047207 DOI: 10.1097/mnh.0000000000001066] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025]
Abstract
PURPOSE OF REVIEW Glucagon-like peptide-1 receptor agonists (GLP1RA), initially approved for glycemic control in type 2 diabetes mellitus (T2DM), have emerged as agents for weight loss, cardiovascular and kidney protection. This review summarizes the evidence supporting the benefits of these therapies on cardiorenal outcomes. RECENT FINDINGS Clinical trials have consistently demonstrated reductions in major adverse cardiovascular events with GLP1RA treatments. Recently, the FLOW trial revealed that semaglutide reduced the composite outcome of kidney failure, at least 50% decline in estimated glomerular filtration rate, kidney or cardiovascular mortality by 24% in patients with T2DM, thereby establishing GLP1RA as a pillar of therapy in this population. New evidence suggests favorable effects on kidney endpoints in nondiabetic individuals with overweight or obesity. Dedicated trials have also provided evidence for reduction in the risk for heart failure hospitalization and improvement in symptoms in individuals with heart failure with preserved ejection fraction. Subgroup analyses have suggested that GLP1RAs confer additive cardiorenal benefits irrespective of background medication use. SUMMARY There is increasing evidence that GLP1RA reduces the risk for cardiovascular events, chronic kidney disease progression, and heart failure hospitalizations. Further data on the effect of dual and triple GLP1-based therapies on cardiorenal outcomes is required.
Collapse
Affiliation(s)
- Labib Faruque
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kevin Yau
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
3
|
Diker Cohen T, Rudman Y, Turjeman A, Akirov A, Steinmetz T, Calvarysky B, Dotan I. Glucagon-like peptide 1 receptor agonists and renal outcomes in kidney transplant recipients with diabetes mellitus. DIABETES & METABOLISM 2025; 51:101624. [PMID: 39961479 DOI: 10.1016/j.diabet.2025.101624] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2024] [Revised: 02/06/2025] [Accepted: 02/08/2025] [Indexed: 02/23/2025]
Abstract
AIMS Glucagon-like peptide-1 receptor agonists (GLP1-RAs) show reno-protective effects in type 2 diabetes. Limited data is available on their use in post-transplant diabetes mellitus. We aimed to explore the effect of GLP1-RAs on renal outcomes in diabetic kidney transplant recipients (KTR). METHODS We conducted a cohort retrospective study on adult KTR with diabetes mellitus. KTR treated with GLP1-RAs were matched with non-users. The primary outcome was the first occurrence of graft rejection, start of dialysis, re-transplantation or all-cause mortality. Other outcomes included a composite of the first occurrence of a genitourinary infection or all-cause mortality, and all-cause mortality. Metabolic effects of GLP1-RA treatment and risk for biliopancreatic adverse events were also explored. RESULTS We included 272 patients (69 % males, average age 58.3 ± 11.0 years) with a 3.1-year median follow-up. The use of GLP1-RAs lowered the incidence of the composite renal outcome after adjustment for independent risk factors (114 versus 68 events per 1000-patient years in controls versus GLP1-RA users, HR 0.489, 95 % CI 0.271-0.883). GLP-RA users had improved glycemic control, lipid profile and a decrease in body mass index. The treatment was safe without increased genitourinary infections or biliopancreatic events. CONCLUSION The use of GLP1-RAs decreased the risk of a composite outcome of renal dysfunction and mortality, improved metabolic control and showed safety of use in a large cohort of diabetic KTR, suggesting reno-protective effects in this high-risk population. Prospective data is further needed in KTR who are excluded from large RCTs.
Collapse
Affiliation(s)
- Talia Diker Cohen
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
| | - Yaron Rudman
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Turjeman
- Research authority, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Amit Akirov
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tali Steinmetz
- Institute of Nephrology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Bronya Calvarysky
- Pharmacy, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Idit Dotan
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel; Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
4
|
Chowdhury TA, Mukuba D, Casabar M, Byrne C, Yaqoob MM. Management of diabetes in people with advanced chronic kidney disease. Diabet Med 2025; 42:e15402. [PMID: 38992927 DOI: 10.1111/dme.15402] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/28/2024] [Accepted: 06/24/2024] [Indexed: 07/13/2024]
Abstract
Diabetes is the commonest cause of end stage kidney disease globally, accounting for almost 40% of new cases requiring renal replacement therapy. Management of diabetes in people with advanced kidney disease on renal replacement therapy is challenging due to some unique aspects of assessment and treatment in this group of patients. Standard glycaemic assessment using glycated haemoglobin may not be valid in such patients due to altered red blood cell turnover or iron/erythropoietin deficiency, leading to changed red blood cell longevity. Therefore, use of continuous glucose monitoring may be beneficial to enable more focussed glycaemic assessment and improved adjustment of therapy. People with advanced kidney disease may be at higher risk of hypoglycaemia due to a number of physiological mechanisms, and in addition, therapeutic options are limited in such patients due to lack of experience or license. Insulin therapy is the basis of treatment of people with diabetes with advanced kidney disease due to many other drugs classes being contraindicated. Targets for glycaemic control should be adjusted according to co-morbidity and frailty, and continuous glucose monitoring should be used in people on dialysis to ensure low risk of hypoglycaemia. Post-transplant diabetes is common amongst people undergoing solid organ transplantation and confers a greater risk of mortality and morbidity in kidney transplant recipients. It should be actively screened for and managed in the post-transplant setting.
Collapse
Affiliation(s)
| | - Dorcas Mukuba
- Department of Diabetes, The Royal London Hospital, London, UK
| | - Mahalia Casabar
- Department of Nephrology, The Royal London Hospital, London, UK
| | - Conor Byrne
- Department of Nephrology, The Royal London Hospital, London, UK
| | - M Magdi Yaqoob
- Barts and the London School of Medicine and Dentistry, London, UK
| |
Collapse
|
|
5
|
American Diabetes Association Professional Practice Committee, ElSayed NA, McCoy RG, Aleppo G, Bajaj M, Balapattabi K, Beverly EA, Briggs Early K, Bruemmer D, Echouffo-Tcheugui JB, Ekhlaspour L, Gaglia JL, Garg R, Girotra M, Khunti K, Lal R, Lingvay I, Matfin G, Neumiller JJ, Pandya N, Pekas EJ, Pilla SJ, Polsky S, Segal AR, Seley JJ, Stanton RC, Bannuru RR. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes-2025. Diabetes Care 2025; 48:S181-S206. [PMID: 39651989 PMCID: PMC11635045 DOI: 10.2337/dc25-s009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2024]
Abstract
The American Diabetes Association (ADA) "Standards of Care in Diabetes" includes the ADA's current clinical practice recommendations and is intended to provide the components of diabetes care, general treatment goals and guidelines, and tools to evaluate quality of care. Members of the ADA Professional Practice Committee, an interprofessional expert committee, are responsible for updating the Standards of Care annually, or more frequently as warranted. For a detailed description of ADA standards, statements, and reports, as well as the evidence-grading system for ADA's clinical practice recommendations and a full list of Professional Practice Committee members, please refer to Introduction and Methodology. Readers who wish to comment on the Standards of Care are invited to do so at professional.diabetes.org/SOC.
Collapse
|
|
6
|
Cigrovski Berkovic M, Šeša V, Balen I, Lai Q, Silovski H, Mrzljak A. Key challenges of post-liver transplant weight management. World J Transplant 2024; 14:95033. [PMID: 39697459 PMCID: PMC11438933 DOI: 10.5500/wjt.v14.i4.95033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 08/21/2024] [Accepted: 09/09/2024] [Indexed: 09/20/2024] Open
Abstract
Liver transplantation serves as a life-saving intervention for patients with end-stage liver disease, yet long-term survival remains a challenge. Post-liver transplant obesity seems to have a significant contribution to this challenge and it emerges as a significant risk factor for graft steatosis, metabolic syndrome and de-novo malignancy development. This review synthesizes current literature on prevalence, risk factors and management strategies for post-liver transplant obesity, emphasizing its impact on graft and patient survival. Literature review consultation was conducted in Medline/PubMed, SciELO and EMBASE, with the combination of the following keywords: Weight management, liver transplantation, immunosuppressive therapy, lifestyle interventions, bariatric surgery. Immunosuppressive therapy has a significant influence on long-term survival of liver transplant patients, yet it seems to have lesser effect on post-transplant obesity development than previously thought. However, it significantly contributes to the development of other components of metabolic syndrome. Key predisposing factors for post-transplant obesity development encompass elevated recipient and donor body mass index, a history of alcoholic liver disease, hepatocellular carcinoma, male gender, the absence of cellular rejection and the marital status of the recipient. Tailored immunosuppressive regimens, pharmacotherapy, lifestyle interventions and bariatric surgery represent key components in mitigating post-transplant obesity and improving long-term survival and quality of life in this group of patients. Timely identification and intervention thus hold paramount importance. Further research is warranted to refine optimal management strategies and enhance outcomes in this patient population.
Collapse
Affiliation(s)
- Maja Cigrovski Berkovic
- Department for Sport and Exercise Medicine, University of Zagreb, Faculty of Kinesiology, Zagreb 10000, Croatia
| | - Vibor Šeša
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
| | - Ivan Balen
- Department of Gastroenterology and Endocrinology, General Hospital “Dr. Josip Bencevic”, Slavonski Brod 35000, Croatia
| | - Quirino Lai
- General Surgery and Organ Transplantation Unit, Department of Surgery, Sapienza University of Rome, Rome 00018, Italy
| | - Hrvoje Silovski
- Department of Hepatobiliary Surgery and Transplantation, University Hospital Center Zagreb, Zagreb 10000, Croatia
| | - Anna Mrzljak
- Department of Gastroenterology and Hepatology, University Hospital Centre Zagreb, Zagreb 10000, Croatia
- Department of Medicine, University of Zagreb, School of Medicine, Zagreb 10000, Croatia
| |
Collapse
|
|
7
|
Riehl-Tonn VJ, Medak KD, Rampersad C, MacPhee A, Harrison TG. GLP-1 Agonism for Kidney Transplant Recipients: A Narrative Review of Current Evidence and Future Directions Across the Research Spectrum. Can J Kidney Health Dis 2024; 11:20543581241290317. [PMID: 39492845 PMCID: PMC11528610 DOI: 10.1177/20543581241290317] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 08/25/2024] [Indexed: 11/05/2024] Open
Abstract
Purpose of Review Diabetes is the most common cause of kidney disease in individuals that receive a kidney transplant, and those without pre-existing diabetes are at greater risk of developing diabetes following kidney transplant. A class of diabetes treatment medications called glucagon-like peptide-1 receptor agonists (GLP-1RA) has seen recent widespread use for people with diabetes or obesity, with efficacy for improved glycemic control, weight loss, and reduced risk of cardiovascular events. Given these benefits, and indications for use that often co-occur in kidney transplant recipients, use of GLP-1RAs warrants consideration in this population. Therefore, we sought to review the current literature to better understand the mechanisms of action, clinical application, and person-centred considerations of GLP-1RAs in kidney transplant recipients. Sources of Information Original articles were identified between December 2023 and July 2024 from electronic databases including the Ovid MEDLINE database, PubMed, and Google Scholar using terms "kidney transplant," "GLP-1," "glucagon-like peptide-1 receptor agonist," and "diabetes." Methods A comprehensive review of the literature was conducted to explore the relationship between GLP-1RAs and kidney transplant recipients. We reviewed the current state of evidence across the research disciplines of basic or fundamental science, clinical and health services research, and person-centred equity science, and highlighted important knowledge gaps that offer opportunities for future research. Key Findings Numerous clinical studies have demonstrated the benefit of GLP-1RAs in people with and without diabetic kidney disease, including decreased risk of cardiovascular events. However, there is a paucity of high-quality randomized controlled trials and observational studies analyzing use of GLP-1RAs in kidney transplant recipients. Evidence of benefit in this population is therefore limited to small studies or inferred from research conducted in nontransplant populations. Growing evidence from preclinical and clinical studies may elucidate renoprotective mechanisms of GLP-1RAs and remove barriers to application of these drugs in the transplant recipient population. Individuals who are female, non-white, have lower socioeconomic status, and live in rural communities are at greater risk of diabetes and have lower uptake of GLP-1RAs. There is a need for clinical trials across diverse kidney transplant populations to estimate the efficacy of GLP-1RAs on important health outcomes. Limitations The search strategy for this narrative review may not have been sensitive to identify all relevant articles. Our search was limited to English language articles.
Collapse
Affiliation(s)
- Victoria J. Riehl-Tonn
- Department of Medicine, University of Calgary, AB, Canada
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, AB, Canada
| | - Kyle D. Medak
- Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada
| | - Christie Rampersad
- Ajmera Transplant Centre, Toronto General Hospital, University Health Network, ON, Canada
- Institute of Health Policy, Management and Evaluation, University of Toronto, ON, Canada
| | - Anne MacPhee
- Canadians Seeking Solutions and Innovations to Overcome Chronic Kidney Disease (Can-SOLVE CKD), Vancouver, BC, Canada
| | - Tyrone G. Harrison
- Department of Medicine, University of Calgary, AB, Canada
- Libin Cardiovascular Institute, Cumming School of Medicine, University of Calgary, AB, Canada
- Department of Community Health Sciences, University of Calgary, AB, Canada
- O’Brien Institute for Public Health, Cumming School of Medicine, University of Calgary, AB, Canada
| |
Collapse
|
|
8
|
Bellos I, Lagiou P, Benetou V, Marinaki S. Safety and Efficacy of Sodium-Glucose Transport Protein 2 Inhibitors and Glucagon-like Peptide-1 Receptor Agonists in Diabetic Kidney Transplant Recipients: Synthesis of Evidence. J Clin Med 2024; 13:6181. [PMID: 39458136 PMCID: PMC11508237 DOI: 10.3390/jcm13206181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/09/2024] [Accepted: 10/14/2024] [Indexed: 10/28/2024] Open
Abstract
Background: This systematic review and meta-analysis aimed to evaluate the efficacy and safety of novel antidiabetics, namely, sodium-glucose transport protein 2 inhibitors (SGLT2-i) and glucagon-like peptide-1 receptor agonists (GLP1-RA), in diabetic kidney transplant recipients. Methods: Medline, Scopus, Web of Science, CENTRAL, and Clinicaltrials.gov were systematically searched from inception until 25 August 2024. Pooled estimates were obtained by applying random-effects models. Results: Overall, 18 studies (17 observational studies and one randomized controlled trial) were included. GLP1-RA were administered to 270 and SGLT2-i to 1003 patients. After GLP1-RA therapy, patients presented significantly lower glycated hemoglobin [mean difference (MD): -0.61%; 95% confidence interval (CI): -0.99; -0.23] and body weight (MD: -3.32 kg; 95% CI: -5.04; -1.59) but a similar estimated glomerular filtration rate (eGFR) and systolic blood pressure. After SGLT2-i therapy, patients had significantly lower glycated hemoglobin (MD: -0.40%, 95% CI: -0.57; -0.23) and body weight (MD: -2.21 kg, 95% CI: -2.74; -1.67), while no difference was noted in eGFR or systolic blood pressure. Preliminary data have shown an association between SGLT2-i use and a reduced risk of cardiovascular events, graft loss, and mortality. Evidence regarding the association between GLP1-RA and SGLT2-i and proteinuria was mixed. No significant effects on calcineurin inhibitor levels were observed. The risk of urinary tract infections was similar among patients treated with SGLT2-i or placebo (odds ratio: 0.84, 95% CI: 0.43; 1.64). Conclusions: Observational data suggest that GLP1-RA and SGLT2-i administration in diabetic kidney transplant recipients may be associated with better glycemic control and reduced body weight, presenting an acceptable safety profile.
Collapse
Affiliation(s)
- Ioannis Bellos
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
- Department of Nephrology and Renal Transplantation, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Pagona Lagiou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
| | - Vassiliki Benetou
- Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, National and Kapodistrian University of Athens, 75, Mikras Asias Str., 115 27 Athens, Greece (V.B.)
| | - Smaragdi Marinaki
- Department of Nephrology and Renal Transplantation, Laiko General Hospital, School of Medicine, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| |
Collapse
|
|
9
|
Zheng K, Azhie A, You X, Naghibzadeh M, Tan E, Naimimohasses S, Sridhar VS, Gupta S, Chen S, Dash S, Tsien C, Selzner N, Lilly L, Jaeckel E, Woo M, Singh S, Cherney D, Bhat M. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter-2 inhibitors for the treatment of diabetes mellitus in liver transplant recipients. Diabetes Obes Metab 2024; 26:4261-4272. [PMID: 39056216 DOI: 10.1111/dom.15769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2024] [Revised: 06/20/2024] [Accepted: 06/20/2024] [Indexed: 07/28/2024]
Abstract
AIM To investigate the efficacy and safety of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors in liver transplant (LT) recipients with diabetes. METHODS A single-centre, retrospective analysis of prospectively collected data from an LT recipient database (1990-2023) was conducted. We included adults with pre-existing diabetes and post-transplant diabetes, newly started on GLP-1RAs and/or SGLT2 inhibitors after LT. Metabolic and biochemical parameters and outcomes were collected for up to 12 months after starting medications and were compared to those in patients receiving dipeptidyl peptidase-4 (DPP-4) inhibitors. Statistical analysis included descriptive statistics and linear mixed models. RESULTS We included participants on GLP-1RAs (n = 46), SGLT2 inhibitors (n = 87), combination therapy (n = 12), and a DPP-4 inhibitor comparator (n = 217). Both GLP-1RAs and combination therapy decreased mean glycated haemoglobin (HbA1c) levels, and combination therapy remained significant when adjusted for DPP-4 inhibitor treatment (-3.5%, 95% CI [-6.1, -0.95]; p = 0.0089) at 12 months. All three groups had significant decreases in mean weight and body mass index, but these remained significant in the GLP-1RA (-5.2 kg, 95% CI [-8.7, -1.7], p = 0.0039 and 1.99 kg/m2, 95% CI [-3.4, -0.6], p = 0.0048) and combination therapy groups (-5.4 kg, 95% CI [-10.5, -0.36], p = 0.04 and -3.4 kg/m2, 95% CI [-5.5, -1.3], p = 0.0015) when adjusted for DPP-4 inhibitor treatment at 12 months. Alanine aminotransferase levels decreased with GLP-1RA and combination therapy. There were two (1.4%) cases of graft rejection. CONCLUSION We found that GLP-1RAs, SGLT2 inhibitors, and their combination, led to significant weight loss in LT recipients with diabetes. Combination therapy, in particular, lowered HbA1c and alanine aminotransferase levels compared to DPP-4 inhibitors. Further studies are needed to assess long-term safety and efficacy.
Collapse
Affiliation(s)
- Katina Zheng
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Amirhossein Azhie
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Xiaoting You
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Maryam Naghibzadeh
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Eunice Tan
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Sara Naimimohasses
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Vikas S Sridhar
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Sarang Gupta
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Shiyi Chen
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Satya Dash
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
| | - Cynthia Tsien
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| | - Nazia Selzner
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| | - Leslie Lilly
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| | - Elmar Jaeckel
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| | - Minna Woo
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University Health Network, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, University of Toronto, Toronto, Ontario, Canada
| | - Sunita Singh
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - David Cherney
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Division of Nephrology, University of Toronto, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University Health Network, Toronto, Ontario, Canada
- Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
10
|
Tacke F, Horn P, Wai-Sun Wong V, Ratziu V, Bugianesi E, Francque S, Zelber-Sagi S, Valenti L, Roden M, Schick F, Yki-Järvinen H, Gastaldelli A, Vettor R, Frühbeck G, Dicker D. EASL-EASD-EASO Clinical Practice Guidelines on the management of metabolic dysfunction-associated steatotic liver disease (MASLD). J Hepatol 2024; 81:492-542. [PMID: 38851997 DOI: 10.1016/j.jhep.2024.04.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2024] [Accepted: 04/30/2024] [Indexed: 06/10/2024]
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.
Collapse
|
|
11
|
Dotan I, Rudman Y, Turjeman A, Akirov A, Steinmetz T, Calvarysky B, Diker Cohen T. Glucagon-like Peptide 1 Receptor Agonists and Cardiovascular Outcomes in Solid Organ Transplant Recipients With Diabetes Mellitus. Transplantation 2024; 108:e121-e128. [PMID: 38361246 DOI: 10.1097/tp.0000000000004945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/17/2024]
Abstract
BACKGROUND Glucagon-like peptide 1 receptor agonists (GLP1-RAs) reduce cardiovascular events and mortality in type 2 diabetes. Limited data are available on diabetes treatment after solid organ transplantation. We aimed to explore the effect of GLP1-RAs on cardiovascular outcomes in transplanted recipients with diabetes. METHODS We extracted data on adult transplant recipients (kidney, lungs, liver, heart) insured in a large health maintenance organization. Death-censored patients with diabetes treated with GLP1-RAs were matched with nonusers. The primary outcome was a composite of major cardiovascular events (MACEs): a nonfatal cardiac event (myocardial infarction, stable/unstable angina, coronary bypass, and coronary angiography), ischemic stroke and all-cause mortality. Secondary outcomes were MACE or peripheral vascular disease (MACE-PVD), and all-cause mortality. Safety outcomes included biliopancreatic adverse events. RESULTS We included 318 patients (69% males, average age 58.3 ± 11.0 y) with a 3.1-y median follow-up. The incidence of MACE was 101 of 1000 patient-years in GLP1-RAs users compared with 134 of 1000 in controls (hazard ratio [HR] 0.46; 95% confidence interval [CI], 0.27-0.78). GLP1-RAs similarly reduced the risk of MACE-PVD (HR 0.53; 95% CI, 0.33-0.88) and the risk of all-cause mortality (HR 0.39; 95% CI, 0.18-0.84). Biliopancreatic adverse events occurred less in GLP1-RA users. CONCLUSIONS Transplant recipients with diabetes who used GLP1-RAs had lower risks for MACE and all-cause mortality. These results may profoundly implicate the daily management of posttransplant recipients with diabetes, a population with a high prevalence of cardiometabolic risk factors and cardiovascular death. Transplant patients are usually excluded from randomized controlled trials and, hence might be undertreated with disease-modifying drugs. Larger prospective studies are needed in this unique population.
Collapse
Affiliation(s)
- Idit Dotan
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Yaron Rudman
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Adi Turjeman
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Research Authority, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Amit Akirov
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Tali Steinmetz
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Institute of Nephrology, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
| | - Bronya Calvarysky
- Pharmacy, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Talia Diker Cohen
- Institute of Endocrinology, Diabetes and Metabolism, Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel
- Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| |
Collapse
|
|
12
|
Kanbay M, Copur S, Topçu AU, Guldan M, Ozbek L, Gaipov A, Ferro C, Cozzolino M, Cherney DZI, Tuttle KR. An update review of post-transplant diabetes mellitus: Concept, risk factors, clinical implications and management. Diabetes Obes Metab 2024; 26:2531-2545. [PMID: 38558257 DOI: 10.1111/dom.15575] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Revised: 03/09/2024] [Accepted: 03/09/2024] [Indexed: 04/04/2024]
Abstract
OBJECTIVE Kidney transplantation is the gold standard therapeutic alternative for patients with end-stage renal disease; nevertheless, it is not without potential complications leading to considerable morbidity and mortality such as post-transplant diabetes mellitus (PTDM). This narrative review aims to comprehensively evaluate PTDM in terms of its diagnostic approach, underlying pathophysiological pathways, epidemiological data, and management strategies. METHODS Articles were retrieved from electronic databases using predefined search terms. Inclusion criteria encompassed studies investigating PTDM diagnosis, pathophysiology, epidemiology, and management strategies. RESULTS PTDM emerges as a significant complication following kidney transplantation, influenced by various pathophysiological factors including peripheral insulin resistance, immunosuppressive medications, infections, and proinflammatory pathways. Despite discrepancies in prevalence estimates, PTDM poses substantial challenges to transplant. Diagnostic approaches, including traditional criteria such as fasting plasma glucose (FPG) and HbA1c, are limited in their ability to capture early PTDM manifestations. Oral glucose tolerance test (OGTT) emerges as a valuable tool, particularly in the early post-transplant period. Management strategies for PTDM remain unclear, within sufficient evidence from large-scale randomized clinical trials to guide optimal interventions. Nevertheless, glucose-lowering agents and life style modifications constitute primary modalities for managing hyperglycemia in transplant recipients. DISCUSSION The complex interplay between PTDM and the transplant process necessitates individualized diagnostic and management approaches. While early recognition and intervention are paramount, modifications to maintenance immunosuppressive regimens based solely on PTDM risk are not warranted, given the potential adverse consequences such as increased rejection risk. Further research is essential to refine management strategies and enhance outcomes for transplant recipients.
Collapse
Affiliation(s)
- Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Sidar Copur
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - A Umur Topçu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Mustafa Guldan
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Lasin Ozbek
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Abduzhappar Gaipov
- Department of Medicine, School of Medicine, Nazarbayev University, Astana, Kazakhstan
| | - Charles Ferro
- Department of Nephrology, University Hospitals Birmingham and Institute of Cardiovascular Sciences, University of Birmingham, Birmingham, UK
| | - Mario Cozzolino
- Department of Health Sciences, Renal Division, University of Milan, Milan, Italy
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, Toronto, Ontario, Canada
| | - Katherine R Tuttle
- Department of Medicine, Division of Nephrology, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
13
|
Donald EM, Driggin E, Choe J, Batra J, Vargas F, Lindekens J, Fried JA, Raikhelkar JK, Bae DJ, Oh KT, Yuzefpolskaya M, Colombo PC, Latif F, Sayer G, Uriel N, Clerkin KJ, DeFilippis EM. Cardio-Renal-Metabolic Outcomes Associated With the Use of GLP-1 Receptor Agonists After Heart Transplantation. Clin Transplant 2024; 38:e15401. [PMID: 39023081 PMCID: PMC11634378 DOI: 10.1111/ctr.15401] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 06/09/2024] [Accepted: 06/24/2024] [Indexed: 07/20/2024]
Abstract
BACKGROUND The use of glucagon-like-peptide 1 receptor agonists (GLP1-RA) has dramatically increased over the past 5 years for diabetes mellitus type 2 (T2DM) and obesity. These comorbidities are prevalent in adult heart transplant (HT) recipients. However, there are limited data evaluating the efficacy of this drug class in this population. The aim of the current study was to describe cardiometabolic changes in HT recipients prescribed GLP1-RA at a large-volume transplant center. METHODS We retrospectively reviewed all adult HT recipients who received GLP1-RA after HT for a minimum of 1-month. Cardiometabolic parameters including body mass index (BMI), lipid panel, hemoglobin A1C, estimated glomerular filtration rate (eGFR), and NT-proBNP were compared prior to initiation of the drug and at most recent follow-up. We also evaluated for significant dose adjustments to immunosuppression after drug initiation and adverse effects leading to drug discontinuation. RESULTS Seventy-four patients were included (28% female, 53% White, 20% Hispanic) and followed for a median of 383 days [IQR 209, 613] on a GLP1-RA. The majority of patients (n = 56, 76%) were prescribed semaglutide. The most common indication for prescription was T2DM alone (n = 33, 45%), followed by combined T2DM and obesity (n = 26, 35%). At most recent follow-up, mean BMI decreased from 33.3 to 31.5 kg/m2 (p < 0.0001), HbA1C from 7.3% to 6.7% (p = 0.005), LDL from 78.6 to 70.3 mg/dL (p = 0.018) and basal insulin daily dose from 32.6 to 24.8 units (p = 0.0002). CONCLUSION HT recipients prescribed GLP1-RA therapy showed improved glycemic control, weight loss, and cholesterol levels during the study follow-up period. GLP1-RA were well tolerated and were rarely associated with changes in immunosuppression dosing.
Collapse
Affiliation(s)
- Elena M Donald
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Elissa Driggin
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Jason Choe
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Jaya Batra
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Fabian Vargas
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Jordan Lindekens
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Justin A Fried
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Jayant K Raikhelkar
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - David J Bae
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Kyung T Oh
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Melana Yuzefpolskaya
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Paolo C Colombo
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Farhana Latif
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Gabriel Sayer
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Nir Uriel
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Kevin J Clerkin
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| | - Ersilia M DeFilippis
- Department of Medicine, Division of Cardiology New York Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA
| |
Collapse
|
|
14
|
EASL-EASD-EASO Clinical Practice Guidelines on the Management of Metabolic Dysfunction-Associated Steatotic Liver Disease (MASLD). Obes Facts 2024; 17:374-444. [PMID: 38852583 PMCID: PMC11299976 DOI: 10.1159/000539371] [Citation(s) in RCA: 18] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Accepted: 05/15/2024] [Indexed: 06/11/2024] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously termed non-alcoholic fatty liver disease (NAFLD), is defined as steatotic liver disease (SLD) in the presence of one or more cardiometabolic risk factor(s) and the absence of harmful alcohol intake. The spectrum of MASLD includes steatosis, metabolic dysfunction-associated steatohepatitis (MASH, previously NASH), fibrosis, cirrhosis and MASH-related hepatocellular carcinoma (HCC). This joint EASL-EASD-EASO guideline provides an update on definitions, prevention, screening, diagnosis and treatment for MASLD. Case-finding strategies for MASLD with liver fibrosis, using non-invasive tests, should be applied in individuals with cardiometabolic risk factors, abnormal liver enzymes, and/or radiological signs of hepatic steatosis, particularly in the presence of type 2 diabetes (T2D) or obesity with additional metabolic risk factor(s). A stepwise approach using blood-based scores (such as FIB-4) and, sequentially, imaging techniques (such as transient elastography) is suitable to rule-out/in advanced fibrosis, which is predictive of liver-related outcomes. In adults with MASLD, lifestyle modification - including weight loss, dietary changes, physical exercise and discouraging alcohol consumption - as well as optimal management of comorbidities - including use of incretin-based therapies (e.g. semaglutide, tirzepatide) for T2D or obesity, if indicated - is advised. Bariatric surgery is also an option in individuals with MASLD and obesity. If locally approved and dependent on the label, adults with non-cirrhotic MASH and significant liver fibrosis (stage ≥2) should be considered for a MASH-targeted treatment with resmetirom, which demonstrated histological effectiveness on steatohepatitis and fibrosis with an acceptable safety and tolerability profile. No MASH-targeted pharmacotherapy can currently be recommended for the cirrhotic stage. Management of MASH-related cirrhosis includes adaptations of metabolic drugs, nutritional counselling, surveillance for portal hypertension and HCC, as well as liver transplantation in decompensated cirrhosis.
Collapse
|
|
15
|
Otero Sanchez L, Chen Y, Lassailly G, Qi X. Exploring the links between types 2 diabetes and liver-related complications: A comprehensive review. United European Gastroenterol J 2024; 12:240-251. [PMID: 38103189 PMCID: PMC10954434 DOI: 10.1002/ueg2.12508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Accepted: 10/24/2023] [Indexed: 12/18/2023] Open
Abstract
In recent decades, the prevalence of type 2 diabetes has been steadily increasing, presenting a significant global public health challenge. These epidemiological trends can be attributed to significant lifestyle changes in modern societies, characterized by sedentary behavior and the consumption of hypercaloric, highly processed foods, along with the aging of the human population. As a result, it has become crucial for both public healthcare systems and healthcare providers to prioritize the management of diabetes and identify its systemic consequences. Emerging research has shed light on the links and risks between diabetes and liver events. This comprehensive review aims to explore the complex interplay between type 2 diabetes mellitus and liver-related outcomes, especially hepatocellular carcinoma and cirrhosis, offering insights into effective methods for detecting liver risk in individuals with diabetes. Additionally, the review will assess the various treatments that could hold the potential for positive outcomes in managing both diabetes and metabolic dysfunction-associated steatotic liver disease and liver fibrosis.
Collapse
Affiliation(s)
- Lukas Otero Sanchez
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium
| | - Yuping Chen
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| | - Guillaume Lassailly
- Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, CUB Hôpital Erasme, Université Libre de Bruxelles, Brussels, Belgium
- Service des maladies de l'appareil digestif, hôpital Huriez, CHU de Lille, Université de Lille, Lille, France
| | - Xiaolong Qi
- Center of Portal Hypertension, Department of Radiology, Zhongda Hospital, Medical School, Southeast University, Nanjing, China
| |
Collapse
|
|
16
|
Sharif A, Chakkera H, de Vries APJ, Eller K, Guthoff M, Haller MC, Hornum M, Nordheim E, Kautzky-Willer A, Krebs M, Kukla A, Kurnikowski A, Schwaiger E, Montero N, Pascual J, Jenssen TG, Porrini E, Hecking M. International consensus on post-transplantation diabetes mellitus. Nephrol Dial Transplant 2024; 39:531-549. [PMID: 38171510 PMCID: PMC11024828 DOI: 10.1093/ndt/gfad258] [Citation(s) in RCA: 17] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2023] [Indexed: 01/05/2024] Open
Abstract
Post-transplantation diabetes mellitus (PTDM) remains a leading complication after solid organ transplantation. Previous international PTDM consensus meetings in 2003 and 2013 provided standardized frameworks to reduce heterogeneity in diagnosis, risk stratification and management. However, the last decade has seen significant advancements in our PTDM knowledge complemented by rapidly changing treatment algorithms for management of diabetes in the general population. In view of these developments, and to ensure reduced variation in clinical practice, a 3rd international PTDM Consensus Meeting was planned and held from 6-8 May 2022 in Vienna, Austria involving global delegates with PTDM expertise to update the previous reports. This update includes opinion statements concerning optimal diagnostic tools, recognition of prediabetes (impaired fasting glucose and/or impaired glucose tolerance), new mechanistic insights, immunosuppression modification, evidence-based strategies to prevent PTDM, treatment hierarchy for incorporating novel glucose-lowering agents and suggestions for the future direction of PTDM research to address unmet needs. Due to the paucity of good quality evidence, consensus meeting participants agreed that making GRADE (Grading of Recommendations, Assessment, Development, and Evaluations) recommendations would be flawed. Although kidney-allograft centric, we suggest that these opinion statements can be appraised by the transplantation community for implementation across different solid organ transplant cohorts. Acknowledging the paucity of published literature, this report reflects consensus expert opinion. Attaining evidence is desirable to ensure establishment of optimized care for any solid organ transplant recipient at risk of, or who develops, PTDM as we strive to improve long-term outcomes.
Collapse
Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, University Hospitals Birmingham, Birmingham, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| | - Harini Chakkera
- Division of Nephrology and Hypertension, Mayo Clinic, Scottsdale, AZ, United States of America
| | - Aiko P J de Vries
- Leiden Transplant Center, Leiden University Medical Center, Leiden, The Netherlands
- Department of Nephrology, Leiden University Medical Center, Leiden, The Netherlands
| | - Kathrin Eller
- Division of Nephrology, Department of Internal Medicine, Medical University of Graz, Graz Austria
| | - Martina Guthoff
- Department of Diabetology, Endocrinology, Nephrology, University of Tübingen, Tübingen, Germany
| | - Maria C Haller
- Ordensklinikum Linz, Elisabethinen Hospital, Department of Medicine III, Nephrology, Hypertension, Transplantation, Rheumatology, Geriatrics, Linz, Austria
- Medical University of Vienna, CeMSIIS, Section for Clinical Biometrics, Vienna, Austria
| | - Mads Hornum
- Department of Nephrology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Espen Nordheim
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Nydalen, Norway
- Department of Nephrology, Oslo University Hospital-Ullevål, Oslo, Nydalen, Norway
| | - Alexandra Kautzky-Willer
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Michael Krebs
- Department of Internal Medicine III, Clinical Division of Endocrinology and Metabolism, Medical University of Vienna, Vienna, Austria
| | - Aleksandra Kukla
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, MN, United States of America
- William J. von Liebig Center for Transplantation and Clinical Regeneration, Mayo Clinic, Rochester, MN, United States of America
| | - Amelie Kurnikowski
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
| | - Elisabeth Schwaiger
- Department of Internal Medicine, Brothers of Saint John of God Eisenstadt, Eisenstadt, Austria
| | - Nuria Montero
- Nephrology Department, Hospital Universitari de Bellvitge, L’Hospitalet de Llobregat, Barcelona, Spain Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, University of Barcelona, Barcelona Spain
| | - Julio Pascual
- Institute Mar for Medical Research-IMIM, Barcelona,Spain
- Department of Nephrology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Trond G Jenssen
- Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Nydalen, Norway
- Institute of Clinical Medicine, University of Oslo, Oslo, Norway
| | - Esteban Porrini
- Instituto de Tecnologías Biomédicas (ITB), University of La Laguna, Research Unit Department, Hospital Universitario de Canarias, Tenerife, Spain
| | - Manfred Hecking
- Department of Internal Medicine III, Clinical Division of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria
- Center for Public Health, Department of Epidemiology, Medical University of Vienna, Vienna, Austria
- Kuratorium for Dialysis and Kidney Transplantation (KfH), Neu-Isenburg, Germany
| |
Collapse
|
|
17
|
Krisanapan P, Suppadungsuk S, Sanpawithayakul K, Thongprayoon C, Pattharanitima P, Tangpanithandee S, Mao MA, Miao J, Cheungpasitporn W. Safety and efficacy of glucagon-like peptide-1 receptor agonists among kidney transplant recipients: a systematic review and meta-analysis. Clin Kidney J 2024; 17:sfae018. [PMID: 38410684 PMCID: PMC10896177 DOI: 10.1093/ckj/sfae018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2023] [Indexed: 02/28/2024] Open
Abstract
Background Evidence supporting glucagon-like peptide-1 receptor agonists (GLP-1RAs) in kidney transplant recipients (KTRs) remains scarce. This systematic review and meta-analysis aims to evaluate the safety and efficacy of GLP-1RAs in this population. Methods A comprehensive literature search was conducted in the MEDLINE, Embase and Cochrane databases from inception through May 2023. Clinical trials and observational studies that reported on the safety or efficacy outcomes of GLP-1RAs in adult KTRs were included. Kidney graft function, glycaemic and metabolic parameters, weight, cardiovascular outcomes and adverse events were evaluated. Outcome measures used for analysis included pooled odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous outcomes and standardized mean difference (SMD) or mean difference (MD) with 95% CI for continuous outcomes. The protocol was registered in the International Prospective Register of Systematic Reviews (CRD 42023426190). Results Nine cohort studies with a total of 338 KTRs were included. The median follow-up was 12 months (interquartile range 6-23). While treatment with GLP-1RAs did not yield a significant change in estimated glomerular filtration rate [SMD -0.07 ml/min/1.73 m2 (95% CI -0.64-0.50)] or creatinine [SMD -0.08 mg/dl (95% CI -0.44-0.28)], they were associated with a significant decrease in urine protein:creatinine ratio [SMD -0.47 (95% CI -0.77 to -0.18)] and haemoglobin A1c levels [MD -0.85% (95% CI -1.41 to -0.28)]. Total daily insulin dose, weight and body mass index also decreased significantly. Tacrolimus levels remained stable [MD -0.43 ng/ml (95% CI -0.99 to 0.13)]. Side effects were primarily nausea and vomiting (17.6%), diarrhoea (7.6%) and injection site pain (5.4%). Conclusions GLP-1RAs are effective in reducing proteinuria, improving glycaemic control and supporting weight loss in KTRs, without altering tacrolimus levels. Gastrointestinal symptoms are the main side effects.
Collapse
Affiliation(s)
- Pajaree Krisanapan
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
- Division of Nephrology, Department of Internal Medicine, Thammasat University Hospital, Pathum Thani, Thailand
| | - Supawadee Suppadungsuk
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan Thailand
| | - Kanokporn Sanpawithayakul
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
- Department of Clinical Epidemiology, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Charat Thongprayoon
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Pattharawin Pattharanitima
- Division of Nephrology, Department of Internal Medicine, Faculty of Medicine, Thammasat University, Pathum Thani, Thailand
| | - Supawit Tangpanithandee
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
- Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan Thailand
| | - Michael A Mao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Jing Miao
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| | - Wisit Cheungpasitporn
- Division of Nephrology and Hypertension, Department of Medicine, Mayo Clinic, Rochester, MN, USA
| |
Collapse
|
|
18
|
Pham NYT, Cruz D, Madera-Marin L, Ravender R, Garcia P. Diabetic Kidney Disease in Post-Kidney Transplant Patients. J Clin Med 2024; 13:793. [PMID: 38337487 PMCID: PMC10856396 DOI: 10.3390/jcm13030793] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2023] [Revised: 01/09/2024] [Accepted: 01/25/2024] [Indexed: 02/12/2024] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common occurrence in post-kidney transplantation and is associated with greater mortality, allograft failure, and increased risk of infections. The primary goal in the management of PTDM is to achieve glycemic control to minimize the risk of complications while balancing the need for immunosuppression to maintain the health of the transplanted kidney. This review summarizes the effects of maintenance immunosuppression and therapeutic options among kidney transplant recipients. Patients with PTDM are at increased risk of diabetic kidney disease development; therefore, in this review, we focus on evidence supporting the use of novel antidiabetic agents and discuss their benefits and potential side effects in detail.
Collapse
Affiliation(s)
- Ngoc-Yen T. Pham
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, NM 87106, USA
| | - Diego Cruz
- Hospital General San Juan de Dios, Guatemala City 01001, Guatemala;
| | - Luis Madera-Marin
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, NM 87106, USA
| | - Raja Ravender
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, NM 87106, USA
| | - Pablo Garcia
- Division of Nephrology, University of New Mexico School of Medicine, Albuquerque, NM 87106, USA
| |
Collapse
|
|
19
|
Munoz Pena JM, Cusi K. Posttransplant Diabetes Mellitus: Recent Developments in Pharmacological Management of Hyperglycemia. J Clin Endocrinol Metab 2023; 109:e1-e11. [PMID: 37410930 DOI: 10.1210/clinem/dgad395] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Revised: 06/20/2023] [Accepted: 06/30/2023] [Indexed: 07/08/2023]
Abstract
CONTEXT The management of solid-organ transplantation is rapidly evolving, and posttransplant diabetes mellitus (PTDM), which is increasingly common, is a barrier to transplant success, adversely impacting infection rates, allograft survival, cardiovascular disease, quality of life, and overall mortality. Currently, the management of PTDM relies primarily on intensified insulin therapy. However, emerging studies report that several noninsulin glucose-lowering agents are safe and effective in improving metabolic control and enhancing treatment adherence. More importantly, their use in PTDM can potentially transform the long-term management of these complex patients, as some glucose-lowering agents may provide benefits beyond glycemic control. For instance, glucagon-like peptide 1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 (SGLT-2) inhibitors may offer cardiorenal protection, and pioglitazone may treat nonalcoholic fatty liver disease (NAFLD). This review will focus on the pharmacological management of PTDM and the emerging evidence for noninsulin glucose-lowering agents in this population. EVIDENCE ACQUISITION Evidence from observational studies, randomized controlled trials, and meta-analyses. EVIDENCE SYNTHESIS PTDM adversely affects the outcomes of infection, organ survival, cardiovascular events, and mortality. Insulin therapy has been the drug of choice but is associated with weight gain and hypoglycemia. In contrast, noninsulin agents appear safe and may provide additional benefits, such as cardiorenal protection with SGLT-2 inhibitors and GLP-1 RA, and cardiometabolic benefits with pioglitazone, in patients undergoing solid-organ transplantation. CONCLUSIONS Optimal care of patients with PTDM requires close monitoring and the early involvement of the endocrinologist as part of a multidisciplinary team. Noninsulin glucose-lowering agents will likely play an increasing role as more long-term, controlled studies become available in this setting.
Collapse
Affiliation(s)
- Juan M Munoz Pena
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL, USA
| | - Kenneth Cusi
- Division of Endocrinology, Diabetes & Metabolism, University of Florida, Gainesville, FL, USA
| |
Collapse
|
|
20
|
Yau K, Odutayo A, Dash S, Cherney DZI. Biology and Clinical Use of Glucagon-Like Peptide-1 Receptor Agonists in Vascular Protection. Can J Cardiol 2023; 39:1816-1838. [PMID: 37429523 DOI: 10.1016/j.cjca.2023.07.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Revised: 06/28/2023] [Accepted: 07/04/2023] [Indexed: 07/12/2023] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP1RA) are incretin agents initially designed for the treatment of type 2 diabetes mellitus but because of pleiotropic actions are now used to reduce cardiovascular disease in people with type 2 diabetes mellitus and in some instances as approved treatments for obesity. In this review we highlight the biology and pharmacology of GLP1RA. We review the evidence for clinical benefit on major adverse cardiovascular outcomes in addition to modulation of cardiometabolic risk factors including reductions in weight, blood pressure, improvement in lipid profiles, and effects on kidney function. Guidance is provided on indications and potential adverse effects to consider. Finally, we describe the evolving landscape of GLP1RA and including novel glucagon-like peptide-1-based dual/polyagonist therapies that are being evaluated for weight loss, type 2 diabetes mellitus, and cardiorenal benefit.
Collapse
Affiliation(s)
- Kevin Yau
- Department of Medicine, Division of Nephrology, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Ayodele Odutayo
- Department of Medicine, Division of Nephrology, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Satya Dash
- Department of Medicine, Division of Nephrology, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David Z I Cherney
- Department of Medicine, Division of Nephrology, University Health Network, and Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
| |
Collapse
|
|
21
|
Atthota S, Joyal K, Cote M, Scalzo R, Singh R, Consul N, Kilcoyne A, Bethea ED, Dageforde LA. Modern glucose-lowering drugs in liver transplant recipients: improvement in weight, glycemic control, and potentially allograft steatosis. FRONTIERS IN TRANSPLANTATION 2023; 2:1223169. [PMID: 38993868 PMCID: PMC11235220 DOI: 10.3389/frtra.2023.1223169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Accepted: 11/13/2023] [Indexed: 07/13/2024]
Abstract
Introduction Recurrent allograft steatosis occurs in one-third of transplanted livers. Antidiabetic agents like glucagon-like peptide-1 receptor agonists (GLP1RA) and sodium-glucose cotransporter type-2 (SGLT2) inhibitors are effective in the management of obesity and hepatic steatosis in the general population; however, there is limited evidence supporting their use in allograft steatosis. We aimed to evaluate their effects on steatosis, body weight, and glycemic control in liver transplant recipients at our institution. Methods In this single-center retrospective cohort study of liver transplant recipients currently on a GLP1RA or SGLT2 inhibitor (transplanted 2015-2022), we compared clinical and radiological data before medication use and at follow-up. Differences were compared using Wilcoxon signed-rank test. Results Thirty-seven liver transplant recipients were taking the agents. Diabetes was the most common indication (n = 33) followed by obesity (n = 4). Median follow up was 427 days (301,798). Among those with documented steatosis (n = 21), steatosis improved in 5, worsened in 4, remained unchanged in 1, and change could not be evaluated in 11 due to lack of comparable pre and post imaging. Average weight loss was 3.2 kg (p < 0.001) and BMI decreased by 1.2 kg/m2 (p < 0.001). Hemoglobin A1c decreased by 0.6 mmol/mol (p = 0.0014), insulin requirement reduced by 7 units/day (p = 0.02), and there was no change in additional antidiabetic medications. Discussion GLP1RA and SGLT-2 inhibitors are tolerated in transplant patients and result in weight loss and better glycemic control. They are promising agents to treat recurrent or de-novo liver allograft steatosis, but further research is needed to evaluate long-term outcomes in liver transplant recipients.
Collapse
Affiliation(s)
- Srilakshmi Atthota
- Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA, United States
| | - Kayla Joyal
- Department of Pharmacy, Massachusetts General Hospital, Boston, MA, United States
| | - Mariesa Cote
- Department of Pharmacy, Massachusetts General Hospital, Boston, MA, United States
| | - Riley Scalzo
- Department of Pharmacy, Massachusetts General Hospital, Boston, MA, United States
| | - Ruby Singh
- Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA, United States
| | - Nikita Consul
- Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
| | - Aoife Kilcoyne
- Department of Radiology, Massachusetts General Hospital, Boston, MA, United States
| | - Emily D. Bethea
- Department of Medicine, Division of Transplant Hepatology, Massachusetts General Hospital, Boston, MA, United States
| | - Leigh Anne Dageforde
- Department of Surgery, Division of Transplantation, Massachusetts General Hospital, Boston, MA, United States
| |
Collapse
|
|
22
|
Clemens KK, Ernst J, Khan T, Reichert S, Khan Q, LaPier H, Chiu M, Stranges S, Sahi G, Castrillon-Ramirez F, Moist L. Glucagon-like peptide 1 receptor agonists in end-staged kidney disease and kidney transplantation: A narrative review. Nutr Metab Cardiovasc Dis 2023; 33:1111-1120. [PMID: 37100640 DOI: 10.1016/j.numecd.2023.03.023] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 03/22/2023] [Accepted: 03/27/2023] [Indexed: 04/28/2023]
Abstract
AIMS Glucagon-like peptide 1 receptor agonists (GLP-1RA) improve glycemic control and promote weight loss in type 2 diabetes (DM2) and obesity. We identified studies describing the metabolic benefits of GLP-1RA in end-staged kidney disease (ESKD) and kidney transplantation. DATA SYNTHESIS We searched for randomized controlled trials (RCTs) and observational studies that investigated the metabolic benefits of GLP-1RA in ESKD and kidney transplantation. We summarized the effect of GLP-1RA on measures of obesity and glycemic control, examined adverse events, and explored adherence with therapy. In small RCTs of patients with DM2 on dialysis, liraglutide for up to 12 weeks lowered HbA1c by 0.8%, reduced time in hyperglycemia by ∼2%, lowered blood glucose by 2 mmol/L and reduced weight by 1-2 kg, compared with placebo. In prospective studies inclusive of ESKD, 12 months of semaglutide reduced HbA1c by 0.8%, and contributed to weight losses of 8 kg. In retrospective cohort studies in DM2 and kidney transplantation, 12 months of GLP-1RA lowered HbA1c by 2%, and fasting glucose by ∼3 mmol/L compared with non-use, and in some reports, weight losses of up to 4 kg were described. Gastrointestinal (GI) side effects were most commonly reported, with hypoglycemia described with GLP-1RA in hemodialysis, particularly in those using insulin. CONCLUSIONS GLP-1RA are growing in popularity in those with DM2 and obesity. In small RCTs and observational cohort studies modest glycemic and weight benefits have been described in ESKD and transplantation, but GI side effects may limit adherence. Larger and longer term studies of GLP-1RA remain important.
Collapse
Affiliation(s)
- Kristin K Clemens
- Department of Medicine, Division of Endocrinology and Metabolism, Western University, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; ICES Western, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada; Lawson Health Research Institute, 750 Base Line Road East, Suite 300, N6C 2R5, London, Ontario, Canada; Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada.
| | - Jaclyn Ernst
- Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Tayyab Khan
- Department of Medicine, Division of Endocrinology and Metabolism, Western University, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada; Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada
| | - Sonja Reichert
- Department of Family Medicine, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada
| | - Qasim Khan
- Department of Medicine, Division of Gastroenterology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Heather LaPier
- Centre for Diabetes, Endocrinology and Metabolism, St. Joseph's Health Care London, 268 Grosvenor Street, N6A 4V2, London, Ontario, Canada
| | - Michael Chiu
- Department of Medicine, Division of Nephrology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| | - Saverio Stranges
- Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Department of Medicine, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada; Department of Family Medicine, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada
| | - Gurleen Sahi
- Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, N6A 5C1, London, Ontario, Canada
| | - Fabio Castrillon-Ramirez
- Schulich School of Medicine and Dentistry, Western University, 1151 Richmond Street, N6A 5C1, London, Ontario, Canada
| | - Louise Moist
- Department of Epidemiology and Biostatistics, Western University, 1465 Richmond Street, N6G 2M1, London, Ontario, Canada; Lawson Health Research Institute, 750 Base Line Road East, Suite 300, N6C 2R5, London, Ontario, Canada; Department of Medicine, Division of Nephrology, Western University, 800 Commissioners Road East, N6A 5W9, London, Ontario, Canada
| |
Collapse
|
|
23
|
Lawrence SE, Chandran MM, Park JM, Sweiss H, Jensen T, Choksi P, Crowther B. Sweet and simple as syrup: A review and guidance for use of novel antihyperglycemic agents for post-transplant diabetes mellitus and type 2 diabetes mellitus after kidney transplantation. Clin Transplant 2023; 37:e14922. [PMID: 36708369 DOI: 10.1111/ctr.14922] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2022] [Revised: 01/16/2023] [Accepted: 01/23/2023] [Indexed: 01/29/2023]
Abstract
Uncontrolled type 2 diabetes mellitus (T2DM) and post-transplant diabetes mellitus (PTDM) increase morbidity and mortality after kidney transplantation. Conventional strategies for diabetes management in this population include metformin, sulfonylureas, meglitinides and insulin. Limitations with these agents, as well as promising new antihyperglycemic agents, create a need and opportunity to explore additional options for transplant diabetes pharmacotherapy. Novel agents including sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP1RA), and dipeptidyl peptidase IV inhibitors (DPP4i) demonstrate great promise for T2DM management in the non-transplant population. Moreover, many of these agents possess renoprotective, cardiovascular, and/or weight loss benefits in addition to improved glucose control while having reduced risk of hypoglycemia compared with certain other conventional agents. This comprehensive review examines available literature evaluating the use of novel antihyperglycemic agents in kidney transplant recipients (KTR) with T2DM or PTDM. Formal grading of recommendations assessment, development, and evaluation (GRADE) system recommendations are provided to guide incorporation of these agents into post-transplant care. Available literature was evaluated to address the clinical questions of which agents provide greatest short- and long-term benefits, timing of novel antihyperglycemic therapy initiation after transplant, monitoring parameters for these antihyperglycemic agents, and concomitant antihyperglycemic agent and immunosuppression regimen management. Current experience with novel antihyperglycemic agents is primarily limited to single-center retrospective studies and case series. With ongoing use and increasing comfort, further and more robust research promises greater understanding of the role of these agents and place in therapy for kidney transplant recipients.
Collapse
Affiliation(s)
- S Elise Lawrence
- Univeristy of Colorado School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.,Department of Pharmacy, University of Colorado Hospital, Aurora, Colorado, USA
| | - Mary Moss Chandran
- Department of Pharmacy, University of North Carolina Medical Center, Chapel Hill, North Carolina, USA
| | - Jeong M Park
- University of Michigan College of Pharmacy, Ann Arbor, Michigan, USA
| | - Helen Sweiss
- Department of Pharmacotherapy and Pharmacy Services, University Health System, San Antonio, Texas
| | - Thomas Jensen
- University of Colorado Department of Medicine - Endocrinology, Diabetes, and Metabolism, Aurora, Colorado, USA
| | - Palak Choksi
- University of Colorado Department of Medicine - Endocrinology, Diabetes, and Metabolism, Aurora, Colorado, USA
| | - Barrett Crowther
- Univeristy of Colorado School of Pharmacy and Pharmaceutical Sciences, Aurora, Colorado, USA.,Department of Pharmacy, University of Colorado Hospital, Aurora, Colorado, USA
| |
Collapse
|
|
24
|
Mallik R, Ali O, Casabar M, Mukuba D, Byrne C, McCafferty K, Yaqoob MM, Chowdhury TA. Glucagon-like peptide-1 receptor analogues in renal transplant recipients with diabetes: Medium term follow of patients from a single UK centre. Diabet Med 2023; 40:e15057. [PMID: 36721974 DOI: 10.1111/dme.15057] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 01/24/2023] [Accepted: 01/30/2023] [Indexed: 02/02/2023]
Affiliation(s)
- Ritwika Mallik
- Department of Diabetes and Metabolism, The Royal London Hospital, London, UK
| | - Omer Ali
- Department of Nephrology, The Royal London Hospital, London, UK
| | - Mahalia Casabar
- Department of Nephrology, The Royal London Hospital, London, UK
| | - Dorcas Mukuba
- Department of Diabetes and Metabolism, The Royal London Hospital, London, UK
| | - Connor Byrne
- Department of Nephrology, The Royal London Hospital, London, UK
| | | | - M Magdi Yaqoob
- Department of Nephrology, The Royal London Hospital, London, UK
| | - Tahseen A Chowdhury
- Department of Diabetes and Metabolism, The Royal London Hospital, London, UK
| |
Collapse
|
|
25
|
Sweiss H, Hall R, Zeilmann D, Escamilla J, Bhayana S, Patel R, Long C. Single-center Evaluation of Safety & Efficacy of Glucagon-Like Peptide-1 Receptor Agonists in Solid Organ Transplantation. Prog Transplant 2022; 32:357-362. [PMID: 36039519 DOI: 10.1177/15269248221122867] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Introduction: Given the negative outcomes associated with uncontrolled diabetes mellitus, non-insulin therapies with glycemic, cardiovascular, and weight-loss benefits in the general population, such as the glucagonlike peptide-1 receptor agonists (GLP1-RA) have become a more alluring therapeutic option in transplant populations. However, limited evidence exists to demonstrate its safety and efficacy in solid organ transplant. Methods: This program evaluation included adult kidney, liver, lung transplant recipients initiated on a GLP1-RA for diabetes mellitus management for a minimum of 3 months, had at least one follow-up visit after starting therapy, and had at least one hemoglobin A1c (HbA1c) level drawn between 3-12 months after GLP1-RA initiation. Outcomes were assessed at time of initiation of GLP1-RA (baseline) and 3-12 months post-initiation. Nadir values between 3-12 months were utilized to assess outcomes. Results: One-hundred eighteen patients met study inclusion criteria. Seventy-percent of patients received a kidney transplant, 19.5% received a liver transplant, and 6.8% received a lung transplant. A statistically significant difference was observed in median fasting blood glucose and HbA1c at baseline to 3-12-month nadir (P < 0.0001). A significant weight loss benefit was also observed. The rate of adverse drug reactions was low. Seven-percent of patients experienced nausea, 4.2% developed pancreatitis, and 7.1% reported having had at least one hypoglycemic event. Discussion: This is the largest study evaluating GLP1-RA in organ transplantation and demonstrates GLP1-RA is both safe and effective. Further assessment on long-term use of these agents on cardiovascular and renal outcomes is still needed.
Collapse
Affiliation(s)
- Helen Sweiss
- Department of Pharmacotherapy & Pharmacy Services, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,University Health Transplant Institute, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,Pharmacotherapy Education and Research Center, 14742The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229 TX, USA.,Pharmacotherapy Division, 15528The University of Texas at Austin, College of Pharmacy, 2409 University Avenue, Austin, 78712 TX, USA
| | - Reed Hall
- Department of Pharmacotherapy & Pharmacy Services, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,University Health Transplant Institute, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,Pharmacotherapy Education and Research Center, 14742The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229 TX, USA.,Pharmacotherapy Division, 15528The University of Texas at Austin, College of Pharmacy, 2409 University Avenue, Austin, 78712 TX, USA
| | - Dominik Zeilmann
- 130378The University of Incarnate Word, Feik School of Pharmacy, 703 E Hildebrand Avenue, San Antonio, 78212 TX, USA
| | - Jesus Escamilla
- 130378The University of Incarnate Word, Feik School of Pharmacy, 703 E Hildebrand Avenue, San Antonio, 78212 TX, USA
| | - Suverta Bhayana
- University Health Transplant Institute, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,Department of Nephrology, 14742The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229 TX, USA
| | - Rupal Patel
- University Health Transplant Institute, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,Department of Nephrology, 14742The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229 TX, USA
| | - Christina Long
- Department of Pharmacotherapy & Pharmacy Services, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,University Health Transplant Institute, 43159University Health System, 4502 Medical Drive, San Antonio, 78229 TX, USA.,Pharmacotherapy Education and Research Center, 14742The University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Drive, San Antonio, 78229 TX, USA.,130378The University of Incarnate Word, Feik School of Pharmacy, 703 E Hildebrand Avenue, San Antonio, 78212 TX, USA
| |
Collapse
|
|
26
|
Sharif A. Interventions Against Posttransplantation Diabetes: A Scientific Rationale for Treatment Hierarchy Based on Literature Review. Transplantation 2022; 106:2301-2313. [PMID: 35696695 DOI: 10.1097/tp.0000000000004198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Posttransplant diabetes (PTD) is a common medical complication after solid organ transplantation. Because of adverse outcomes associated with its development and detrimental impact on long-term survival, strategies to prevent or manage PTD are critically important but remain underresearched. Treatment hierarchies of antidiabetic therapies in the general population are currently being revolutionized based on cardiovascular outcome trials, providing evidence-based rationale for optimization of medical management. However, opportunities for improving medical management of PTD are challenged by 2 important considerations: (1) translating clinical evidence data from the general population to underresearched solid organ transplant cohorts and (2) targeting treatment based on primary underlying PTD pathophysiology. In this article, the aim is to provide an overview of PTD treatment options from a new angle. Rationalized by a consideration of underlying PTD pathophysiological defects, which are heterogeneous among diverse transplant patient cohorts, a critical appraisal of the published literature and summary of current research in progress will be reviewed. The aim is to update transplant professionals regarding medical management of PTD from a new perspective tailored therapeutic intervention based on individualized characteristics. As the gap in clinical evidence between management of PTD versus type 2 diabetes widens, it is imperative for the transplant community to bridge this gap with targeted clinical trials to ensure we optimize outcomes for solid organ transplant recipients who are at risk or develop PTD. This necessary clinical research should help efforts to improve long-term outcomes for solid transplant patients from both a patient and graft survival perspective.
Collapse
Affiliation(s)
- Adnan Sharif
- Department of Nephrology and Transplantation, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom.,Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, United Kingdom
| |
Collapse
|
|
27
|
Sridhar VS, Ambinathan JPN, Gillard P, Mathieu C, Cherney DZI, Lytvyn Y, Singh SK. Cardiometabolic and Kidney Protection in Kidney Transplant Recipients With Diabetes: Mechanisms, Clinical Applications, and Summary of Clinical Trials. Transplantation 2022; 106:734-748. [PMID: 34381005 DOI: 10.1097/tp.0000000000003919] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
Kidney transplantation is the therapy of choice for patients with end-stage renal disease. Preexisting diabetes is highly prevalent in kidney transplant recipients (KTR), and the development of posttransplant diabetes is common because of a number of transplant-specific risk factors such as the use of diabetogenic immunosuppressive medications and posttransplant weight gain. The presence of pretransplant and posttransplant diabetes in KTR significantly and variably affect the risk of graft failure, cardiovascular disease (CVD), and death. Among the many available therapies for diabetes, there are little data to determine the glucose-lowering agent(s) of choice in KTR. Furthermore, despite the high burden of graft loss and CVD among KTR with diabetes, evidence for strategies offering cardiovascular and kidney protection is lacking. Recent accumulating evidence convincingly shows glucose-independent cardiorenal protective effects in non-KTR with glucose-lowering agents, such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists. Therefore, our aim was to review cardiorenal protective strategies, including the evidence, mechanisms, and rationale for the use of these glucose-lowering agents in KTR with diabetes.
Collapse
Affiliation(s)
- Vikas S Sridhar
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Jaya Prakash N Ambinathan
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Pieter Gillard
- Department of Endocrinology, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium
| | - Chantal Mathieu
- Department of Endocrinology, University Hospitals Leuven, Catholic University Leuven, Leuven, Belgium
| | - David Z I Cherney
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yuliya Lytvyn
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| | - Sunita K Singh
- Division of Nephrology, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- The Kidney Transplant Program and the Ajmera Tranplant Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada
| |
Collapse
|
|
28
|
Montero N, Oliveras L, Soler MJ, Cruzado JM. Management of post-transplant diabetes mellitus: an opportunity for novel therapeutics. Clin Kidney J 2022; 15:5-13. [PMID: 35265335 PMCID: PMC8901587 DOI: 10.1093/ckj/sfab131] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2021] [Indexed: 12/16/2022] Open
Abstract
Post-transplant diabetes mellitus (PTDM) is a common problem after kidney transplantation (KT), occurring in 50% of high-risk recipients. The clinical importance of PTDM lies in its impact as a significant risk factor for cardiovascular and chronic kidney disease (CKD) after solid organ transplantation. Kidney Disease: Improving Global Outcomes (KDIGO) has recently updated the treatment guidelines for diabetes management in CKD with emphasis on the newer antidiabetic agents such as dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter 2 inhibitors as add-on therapy to metformin. Given all these new diabetes treatments and the updated KDIGO guidelines, it is necessary to evaluate and give guidance on their use for DM management in KT recipients. This review summarizes the scarce published literature about the use of these new agents in the KT field. In summary, it is absolutely necessary to generate evidence in order to be able to safely use these new treatments in the KT population to improve blood glucose control, but specially to evaluate their potential cardiovascular and renal benefits that would seem to be independent of blood glucose control in PTDM patients.
Collapse
Affiliation(s)
- Nuria Montero
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Laia Oliveras
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| | - Maria José Soler
- Department of Nephrology, Hospital Vall d'Hebron, Barcelona, Spain
| | - Josep Maria Cruzado
- Department of Nephrology, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain
| |
Collapse
|
|
29
|
Vigara LA, Villanego F, Orellana C, Naranjo J, Torrado J, Garcia T, Mazuecos A. Effectiveness and safety of glucagon-like peptide-1 receptor agonist in a cohort of kidney transplant recipients. Clin Transplant 2022; 36:e14633. [PMID: 35258121 DOI: 10.1111/ctr.14633] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 02/25/2022] [Accepted: 03/01/2022] [Indexed: 11/30/2022]
Affiliation(s)
| | | | | | - Javier Naranjo
- Department of Nephrology, Hospital Puerta del Mar, Cadiz, Spain
| | - Julia Torrado
- Department of Nephrology, Hospital Puerta del Mar, Cadiz, Spain
| | - Teresa Garcia
- Department of Nephrology, Hospital Puerta del Mar, Cadiz, Spain
| | | |
Collapse
|
|
30
|
Górriz JL, Romera I, Cobo A, O'Brien PD, Merino-Torres JF. Glucagon-Like Peptide-1 Receptor Agonist Use in People Living with Type 2 Diabetes Mellitus and Chronic Kidney Disease: A Narrative Review of the Key Evidence with Practical Considerations. Diabetes Ther 2022; 13:389-421. [PMID: 35175551 PMCID: PMC8934828 DOI: 10.1007/s13300-021-01198-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Accepted: 12/21/2021] [Indexed: 02/06/2023] Open
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are incretin-mimetic agents that are effective adjuncts in the treatment of diabetes. This class of medications is also associated with promoting weight loss and a low risk of hypoglycemia, and some have been shown to be associated with a significant reduction of major cardiovascular events. Mounting evidence suggests that GLP-1 RAs have benefits beyond reducing blood glucose that include improving kidney function in people living with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD), a common microvascular complication of T2DM. Several large clinical studies, the majority of which are cardiovascular outcome trials, indicate that GLP-1 RA therapy is safe and tolerable for people living with T2DM and compromised renal function, and also suggest that GLP-1 RAs may have renoprotective properties. Although evidence from clinical trials has shown GLP-1 RAs to be safe and efficacious in people living with T2DM and renal impairment, their use is uncommon in this patient population. With continuing developments in the field of GLP-1 RA therapy, it is important for physicians to understand the benefits and practical use of GLP-1 RAs, as well as the clinical evidence, in order to achieve positive patient outcomes. Here, we review evidence on GLP-1 RA use in people living with T2DM and CKD and summarize renal outcomes from clinical studies. We provide practical considerations for GLP-1 RA use to provide an added benefit to guide treatment in this high-risk patient population.
Collapse
Affiliation(s)
- José L Górriz
- Department of Nephrology, Hospital Clínico Universitario de Valencia-INCLIVA, University of Valencia, Valencia, Spain
| | | | | | | | - Juan F Merino-Torres
- Endocrinology and Nutrition Department, Hospital Universitario y Politécnico de La Fe, University of Valencia, Valencia, Spain
| |
Collapse
|
|
31
|
Grundman JB, Wolfsdorf JI, Marks BE. Post-Transplantation Diabetes Mellitus in Pediatric Patients. Horm Res Paediatr 2022; 93:510-518. [PMID: 33789298 DOI: 10.1159/000514988] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Accepted: 01/22/2021] [Indexed: 11/19/2022] Open
Abstract
More than 80% of pediatric solid organ transplant (SOT) recipients now survive into young adulthood and many encounter transplant-related complications. Post-transplantation diabetes mellitus (PTDM), sometimes also referred to as post-transplant diabetes or new onset diabetes after transplant, occurs in 3-20% of pediatric SOT recipients depending upon the organ transplanted, age at transplantation, immunosuppressive regimen, family history, and time elapsed since transplant. To diagnose PTDM, hyperglycemia must persist beyond the initial hospitalization for transplantation when a patient is on stable doses of immunosuppressive medications. Though standard diagnostic criteria used by the American Diabetes Association (ADA) to diagnose diabetes are employed, clinicians need to be aware of the limitations of using these criteria in this unique patient population. Management of PTDM parallels strategies used for type 2 diabetes (T2D), while also carefully considering comorbidities and potential interactions with immunosuppressive medications in these patients. In caring for patients with PTDM, it is important to be familiar with these interactions and comorbidities in order to coordinate care with the transplant team and optimize outcomes for these patients.
Collapse
Affiliation(s)
- Jody B Grundman
- Division of Endocrinology, Children's National Hospital, Washington, District of Columbia, USA
| | - Joseph I Wolfsdorf
- Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts, USA
| | - Brynn E Marks
- Division of Endocrinology, Children's National Hospital, Washington, District of Columbia, USA.,George Washington University School of Medicine, Washington, District of Columbia, USA
| |
Collapse
|
|
32
|
Farwa U, Raza MA. Heterocyclic compounds as a magic bullet for diabetes mellitus: a review. RSC Adv 2022; 12:22951-22973. [PMID: 36105949 PMCID: PMC9379558 DOI: 10.1039/d2ra02697j] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022] Open
Abstract
Diabetes mellitus (DM) is a major metabolic disorder due to hyperglycemia, which is increasing all over the world. From the last two decades, the use of synthetic agents has risen due to their major involvement in curing of chronic diseases including DM. The core skeleton of drugs has been studied such as thiazolidinone, azole, chalcone, pyrrole and pyrimidine along with their derivatives. Diabetics assays have been performed in consideration of different enzymes such as α-glycosidase, α-amylase, and α-galactosidase against acarbose standard drug. The studied moieties were depicted in both models: in vivo as well as in vitro. Molecular docking of the studied compounds as antidiabetic molecules was performed with the help of Auto Dock and molecular operating environment (MOE) software. Amino acid residues Asp349, Arg312, Arg439, Asn241, Val303, Glu304, Phe158, His103, Lys422 and Thr207 that are present on the active sites of diabetic related enzymes showed interactions with ligand molecules. In this review data were organized for the synthesis of heterocyclic compounds through various routes along with their antidiabetic potential, and further studies such as pharmacokinetic and toxicology studies should be executed before going for clinical trials. Diabetes mellitus (DM) is a major metabolic disorder due to hyperglycemia, which is increasing all over the world.![]()
Collapse
Affiliation(s)
- Umme Farwa
- Department of Chemistry, University of Gujrat, Gujrat 50700, Pakistan
| | | |
Collapse
|
|
33
|
Abstract
PURPOSE OF REVIEW Posttransplant diabetes mellitus (PTDM) is a prevalent complication in kidney transplant recipients, and has been associated with worse short-term and long-term outcomes. RECENT FINDINGS While hyperglycemia is frequently seen in the early posttransplant period because of surgical stress, infection, and use of high-dose steroids, the diagnosis of PTDM should be established after patients are clinically stable and on stable maintenance immunosuppression. In the early posttransplant period, hyperglycemia is typically treated with insulin, and pilot data have suggested potential benefit of lower vs. higher glycemic targets in this setting. Growing data indicate lifestyle modifications, including dietary interventions, physical activity, and mitigation of obesity, are associated with improved posttransplant outcomes. While there are limited data to support a first-line antidiabetic medication for PTDM, more established pharmacotherapies such as sulfonylureas, meglitinides, and dipetidyl peptidase IV inhibitors are commonly used. Given recent trials showing the benefits of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists upon kidney outcomes in nontransplant patients, further study of these agents specifically in kidney transplant recipients are urgently needed. SUMMARY Increasing evidence supports a multidisciplinary approach, including lifestyle modification, obesity treatment, judicious immunosuppression selection, and careful utilization of novel antidiabetic therapies in PTDM patients.
Collapse
|
|
34
|
Kim HS, Lee J, Jung CH, Park JY, Lee WJ. Dulaglutide as an Effective Replacement for Prandial Insulin in Kidney Transplant Recipients with Type 2 Diabetes Mellitus: A Retrospective Review. Diabetes Metab J 2021; 45:948-953. [PMID: 33535737 PMCID: PMC8640157 DOI: 10.4093/dmj.2020.0180] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Accepted: 11/11/2020] [Indexed: 11/08/2022] Open
Abstract
Dulaglutide, a weekly injectable glucagon-like peptide-1 receptor agonist, has demonstrated effectiveness when combined with basal insulin. We examined whether the efficacy of dulaglutide is comparable to that of prandial insulin in kidney transplant (KT) recipients with type 2 diabetes mellitus (T2DM) undergoing multiple daily insulin injection (MDI) therapy. Thirty-seven patients, who switched from MDI therapy to basal insulin and dulaglutide, were retrospectively analyzed. Changes in glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels, body weight, and basal insulin dose were evaluated over 6 months. Dulaglutide was comparable to three injections of prandial insulin in terms of glycemic control (HbA1c 7.1% vs. 7.0%; 95% confidence interval [CI], -0.53 to 0.28; P=0.53). The basal insulin and dulaglutide combination resulted in a reduction in FPG levels by 9.7 mg/dL (95% CI, 2.09 to 41.54; P=0.03), in body weight by 4.9 kg (95% CI, 2.87 to 6.98; P<0.001), and in basal insulin dose by 9.52 IU (95% CI, 5.80 to 3.23; P<0.001). Once-weekly dulaglutide may be an effective alternative for thrice-daily prandial insulin in KT recipients with T2DM currently receiving MDI therapy.
Collapse
Affiliation(s)
- Hwi Seung Kim
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
| | - Jiwoo Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
| | - Chang Hee Jung
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
| | - Joong-Yeol Park
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
| | - Woo Je Lee
- Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
- Asan Diabetes Center, Asan Medical Center, Seoul, Korea
| |
Collapse
|
|
35
|
Martinez Cantarin MP. Diabetes in Kidney Transplantation. Adv Chronic Kidney Dis 2021; 28:596-605. [PMID: 35367028 DOI: 10.1053/j.ackd.2021.10.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 10/11/2021] [Accepted: 10/12/2021] [Indexed: 11/11/2022]
Abstract
Diabetes mellitus (DM) is one of the most common complications after kidney transplantation and is associated with unfavorable outcomes including death. DM can be present before transplant but post-transplant DM (PTDM) refers to diabetes that is diagnosed after solid organ transplantation. Despite its high prevalence, optimal treatment to prevent complications of PTDM is unknown. Medical therapy of pre-existent DM or PTDM after transplant is challenging because of frequent interactions between antidiabetic and immunosuppressive agents. There is also frequent need for medication dose adjustments due to residual kidney disease and a higher risk of medication side effects in patients treated with immunosuppressive agents. Sodium-glucose cotransporter 2 inhibitors have demonstrated a favorable cardio-renal profile in patients with DM without a transplant and hence hold great promise in this patient population although there is concern about the higher risk of urinary tract infections. The significant gaps in our understanding of the pathophysiology, diagnosis, and management of DM after kidney transplantation need to be urgently addressed.
Collapse
|
|
36
|
Ben-David E, Hull R, Banerjee D. Diabetes mellitus in dialysis and renal transplantation. Ther Adv Endocrinol Metab 2021; 12:20420188211048663. [PMID: 34631007 PMCID: PMC8495524 DOI: 10.1177/20420188211048663] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Accepted: 08/29/2021] [Indexed: 12/31/2022] Open
Abstract
Diabetes mellitus is the commonest cause of end-stage kidney failure worldwide and is a proven and significant risk factor for the development of cardiovascular disease. Renal impairment has a significant impact on the physiology of glucose homeostasis as it reduces tissue sensitivity to insulin and reduces insulin clearance. Renal replacement therapy itself affects glucose control: peritoneal dialysis may induce hyperglycaemia due to glucose-rich dialysate and haemodialysis often causes hypoglycaemia due to the relatively low concentration of glucose in the dialysate. Autonomic neuropathy which is common in chronic kidney disease (CKD) and diabetes increases the risk for asymptomatic hypoglycaemia. Pharmacological options for improving glycaemic control are limited due to alterations to drug metabolism. Impaired glucose tolerance and diabetes are also common in the post-kidney-transplant setting and increase the risk of graft failure and mortality. This review seeks to summarise the literature and tackle the intricacies of glycaemic management in patients with CKD who are either on maintenance haemodialysis or have received a kidney transplant. It outlines changes to glycaemic targets, monitoring of glycaemic control, the use of oral hypoglycaemic agents, the management of severe hyperglycaemia in dialysis and kidney transplantation patients.
Collapse
Affiliation(s)
- Eyal Ben-David
- Renal and Transplantation Unit, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Richard Hull
- Renal and Transplantation Unit, St George's University Hospitals NHS Foundation Trust, London, UK
| | - Debasish Banerjee
- Renal and Transplantation Unit, St George's University Hospitals NHS Foundation Trust, Room G2.113, Second Floor, Grosvenor Wing, Blackshaw Road, Tooting, London SW17 0QT, UK
| |
Collapse
|
|
37
|
Azhie A, Sheth P, Hammad A, Woo M, Bhat M. Metabolic Complications in Liver Transplantation Recipients: How We Can Optimize Long-Term Survival. Liver Transpl 2021; 27:1468-1478. [PMID: 34165872 DOI: 10.1002/lt.26219] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Revised: 06/14/2021] [Accepted: 06/17/2021] [Indexed: 12/27/2022]
Abstract
Liver transplantation (LT) recipients have experienced a significant improvement in short-term survival during the past 3 decades attributed to advancements in surgical techniques, perioperative management, and effective immunosuppressive regimens. However, long-term survival is affected by a high incidence of metabolic disorders and their consequences, including cardiovascular disease (CVD) and malignancies. Pretransplant metabolic impairments especially in those with nonalcoholic steatohepatitis cirrhosis are aggravated by the addition of posttransplant weight gain, physical inactivity, and reversal from catabolic to anabolic state. Moreover, although immunosuppressants are vital to avoid graft rejection, long-term exposure to these medications is implicated in metabolic impairments after LT. In this review, we summarize the molecular pathogenesis of different metabolic disorders after LT, including diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease. Furthermore, CVD, malignancies, and graft rejections were provided as significant complications of post-LT metabolic conditions threatening both the patient and graft survival. Ultimately, emerging preventive and treatment strategies for posttransplant diabetes mellitus are summarized. This review highlights the significant need for more clinical trials of antihyperglycemic agents in LT recipients. Also, translational studies will help us to better understand the molecular and genetic factors underlying these metabolic complications and could lead to more personalized management in this high-risk population.
Collapse
Affiliation(s)
- Amirhossein Azhie
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Priya Sheth
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada
| | - Ahmed Hammad
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Department of General Surgery, Mansoura University, Mansoura, Egypt
| | - Minna Woo
- Division of Endocrinology and Metabolism, Department of Medicine, University Health Network and Sinai Health System, University of Toronto, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Mamatha Bhat
- Multi Organ Transplant Program, University Health Network, Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Gastroenterology and Hepatology, Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
38
|
Phillips J, Chen JHC, Ooi E, Prunster J, Lim WH. Global Epidemiology, Health Outcomes, and Treatment Options for Patients With Type 2 Diabetes and Kidney Failure. FRONTIERS IN CLINICAL DIABETES AND HEALTHCARE 2021; 2:731574. [PMID: 36994340 PMCID: PMC10012134 DOI: 10.3389/fcdhc.2021.731574] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/27/2021] [Accepted: 07/29/2021] [Indexed: 12/15/2022]
Abstract
The burden of type 2 diabetes and related complications has steadily increased over the last few decades and is one of the foremost global public health threats in the 21st century. Diabetes is one of the leading causes of chronic kidney disease and kidney failure and is an important contributor to the cardiovascular morbidity and mortality in this population. In addition, up to one in three patients who have received kidney transplants develop post-transplant diabetes, but the management of this common complication continues to pose a significant challenge for clinicians. In this review, we will describe the global prevalence and temporal trend of kidney failure attributed to diabetes mellitus in both developing and developed countries. We will examine the survival differences between treated kidney failure patients with and without type 2 diabetes, focusing on the survival differences in those on maintenance dialysis or have received kidney transplants. With the increased availability of novel hypoglycemic agents, we will address the potential impacts of these novel agents in patients with diabetes and kidney failure and in those who have developed post-transplant diabetes.
Collapse
Affiliation(s)
- Jessica Phillips
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- *Correspondence: Jessica Phillips,
| | - Jenny H. C. Chen
- School of Medicine, University of Wollongong, Wollongong, NSW, Australia
- Depatment of Nephrology, Wollongong Hospital, Wollongong, NSW, Australia
| | - Esther Ooi
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Janelle Prunster
- Department of Renal Medicine, Cairns Hospital, Cairns, QLD, Australia
| | - Wai H. Lim
- Department of Renal Medicine, Sir Charles Gairdner Hospital, Perth, WA, Australia
- Medical School, University of Western Australia, Perth, WA, Australia
| |
Collapse
|
|
39
|
Mosenzon O, Schechter M, Leibowitz G. Kidney Outcomes With Glucagon-Like Peptide-1 Receptor Agonists in Patients With Type 2 Diabetes. Adv Chronic Kidney Dis 2021; 28:347-360. [PMID: 34922691 DOI: 10.1053/j.ackd.2021.04.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2021] [Revised: 04/14/2021] [Accepted: 04/23/2021] [Indexed: 01/10/2023]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are highly effective in reducing glycemia in patients with type 2 diabetes (T2D). These medications effectively reduce cardiovascular (CV) risk in patients with T2D and established CV disease or with multiple risk factors. In addition, treatment with GLP-1 RA may exert protective effects on the diabetic kidney. Herein, we summarize the findings regarding the kidney safety and efficacy of GLP-1 RAs in patients with T2D. We review data from GLP-1 RAs phase 3 kidney studies, CV outcome trials, as well as real-world evidence. The accumulating data show that treatment with GLP-1 RAs is safe, well-tolerated, and effective in patients with different levels of kidney dysfunction. Furthermore, CV outcome trials suggest that GLP-1 RAs reduce albuminuria and may attenuate the decline in kidney function over time. The ongoing FLOW trial studying the effects of semaglutide in patients with diabetic kidney disease is expected to shed light on the effects of GLP-1 RAs on kidney outcomes and clarify their role in the management of patients with T2D and kidney disease.
Collapse
|
|
40
|
Nissaisorakarn P, Pavlakis M, Aala A. Novel Glucose-Lowering Therapies in the Setting of Solid Organ Transplantation. Adv Chronic Kidney Dis 2021; 28:361-370. [PMID: 34922692 DOI: 10.1053/j.ackd.2021.03.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/27/2021] [Accepted: 03/01/2021] [Indexed: 11/11/2022]
Abstract
Post-transplant diabetes mellitus is a frequent consequence of or a pre-existing comorbidity in solid organ transplantation (SOT) that is associated with greater morbidity and mortality. Novel glucose-lowering agents that have been shown to have cardiovascular morbidity/mortality benefit and renal protective effects such as sodium glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists are being incorporated into new standard of care for diabetes mellitus. There is a paucity of data regarding the use of these agents in SOT. In this article, we will aim to review available literature on newer glucose-lowering therapeutics in SOT, mainly sodium glucose transporter 2 inhibitors and glucagon-like peptide-1 receptor agonists, their mechanism of action, benefits, risks, and safety profiles.
Collapse
|
|
41
|
Ertuglu LA, Porrini E, Hornum M, Demiray A, Afsar B, Ortiz A, Covic A, Rossing P, Kanbay M. Glucagon-like peptide-1 receptor agonists and sodium-glucose cotransporter 2 inhibitors for diabetes after solid organ transplantation. Transpl Int 2021; 34:1341-1359. [PMID: 33880815 DOI: 10.1111/tri.13883] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/22/2021] [Accepted: 04/12/2021] [Indexed: 12/13/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) is a common complication of solid organ transplantation and a major cause of increased morbidity and mortality. Additionally, solid organ transplant patients may have pre-existent type 2 diabetes mellitus (T2DM). While insulin is the treatment of choice for hyperglycemia in the first weeks after transplantation, there is no preferred first line agent for long-term management of PTDM or pre-existent T2DM. Glucagon-like peptide-1 receptor agonists (GLP-1RA) and sodium-glucose cotransporter 2 (SGLT2) inhibitors improve glycemic control, lower body weight, and blood pressure, are recommended after lifestyle and metformin as initial therapy for diabetic patients with cardiovascular or kidney comorbidities regarding their cardiorenal benefits. Furthermore, the mechanisms of action of GLP-1RA may counteract some of the driving forces for PTDM, as calcineurin-induced β cell toxicity as per preclinical data, and improve obesity. However, their use in the treatment of PTDM is currently limited by a paucity of data. Retrospective observational and small exploratory studies suggest that GLP-1RA effectively improve glycemic control and induce weight loss in patients with PTDM without interacting with commonly used immunosuppressive agents, although randomized-controlled clinical trials are required to confirm their safety and efficacy. In this narrative review, we evaluate the risk factors and pathogenesis of PTDM and compare the potential roles of GLP-1RA and SGLT2 inhibitors in PTDM prevention and management as well as in pre-existent T2DM, and providing a roadmap for evidence generation on newer antidiabetic drugs for solid organ transplantation.
Collapse
Affiliation(s)
- Lale A Ertuglu
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Esteban Porrini
- Red de Investigación Renal (REDINREN), Instituto Carlos III-FEDER, Tenerife, Spain.,Department of Medicine, Hospital Universitario de Canarias, Tenerife, Spain.,Instituto de Tecnologías Biomédicas, University of La Laguna, Tenerife, Spain
| | - Mads Hornum
- Department of Nephrology, Rigshospitalet, Copenhagen, Denmark.,Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Atalay Demiray
- Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| | - Baris Afsar
- Division of Nephrology, Department of Internal Medicine, Suleyman Demirel University School of Medicine, Isparta, Turkey
| | - Alberto Ortiz
- IIS-Fundacion Jimenez Diaz, Department of Medicine, School of Medicine, Universidad Autonoma de Madrid, Madrid, Spain
| | - Adrian Covic
- Department of Nephrology, Grigore T. Popa' University of Medicine, Iasi, Romania
| | - Peter Rossing
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.,Steno Diabetes Center Copenhagen, Copenhagen, Denmark
| | - Mehmet Kanbay
- Division of Nephrology, Department of Medicine, Koc University School of Medicine, Istanbul, Turkey
| |
Collapse
|
|
42
|
Martin-Moreno PL, Shin HS, Chandraker A. Obesity and Post-Transplant Diabetes Mellitus in Kidney Transplantation. J Clin Med 2021; 10:2497. [PMID: 34198724 PMCID: PMC8201168 DOI: 10.3390/jcm10112497] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 05/30/2021] [Accepted: 06/01/2021] [Indexed: 12/14/2022] Open
Abstract
Worldwide, the prevalence obesity, diabetes, and chronic kidney disease is increasing apace. The relationship between obesity and chronic kidney disease is multidimensional, especially when diabetes is also considered. The optimal treatment of patients with chronic kidney disease includes the need to consider weight loss as part of the treatment. The exact relationship between obesity and kidney function before and after transplantation is not as clear as previously imagined. Historically, patients with obesity had worse outcomes following kidney transplantation and weight loss before surgery was encouraged. However, recent studies have found less of a correlation between obesity and transplant outcomes. Transplantation itself is also a risk factor for developing diabetes, a condition known as post-transplant diabetes mellitus, and is related to the use of immunosuppressive medications and weight gain following transplantation. Newer classes of anti-diabetic medications, namely SGLT-2 inhibitors and GLP-1 agonists, are increasingly being recognized, not only for their ability to control diabetes, but also for their cardio and renoprotective effects. This article reviews the current state of knowledge on the management of obesity and post-transplant diabetes mellitus for kidney transplant patients.
Collapse
Affiliation(s)
- Paloma Leticia Martin-Moreno
- Department of Nephrology, Clinica Universidad de Navarra, Navarra Institute for Health Research (IdiSNA), 31008 Pamplona, Spain
| | - Ho-Sik Shin
- Renal Division, Department of Internal Medicine, Gospel Hospital, Kosin University, Busan 49267, Korea;
- Transplantation Research Institute, Kosin University College of Medicine, Busan 49367, Korea
| | - Anil Chandraker
- Renal Division, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA;
| |
Collapse
|
|
43
|
Montada-Atin T, Prasad GVR. Recent advances in new-onset diabetes mellitus after kidney transplantation. World J Diabetes 2021; 12:541-555. [PMID: 33995843 PMCID: PMC8107982 DOI: 10.4239/wjd.v12.i5.541] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/05/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
A common challenge in managing kidney transplant recipients (KTR) is post-transplant diabetes mellitus (PTDM) or diabetes mellitus (DM) newly diagnosed after transplantation, in addition to known pre-existing DM. PTDM is an important risk factor for post-transplant cardiovascular (CV) disease, which adversely affects patient survival and quality of life. CV disease in KTR may manifest as ischemic heart disease, heart failure, and/or left ventricular hypertrophy. Available therapies for PTDM include most agents currently used to treat type 2 diabetes. More recently, the use of sodium glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1 RA), and dipeptidyl peptidase 4 inhibitors (DPP4i) has cautiously extended to KTR with PTDM, even though KTR are typically excluded from large general population clinical trials. Initial evidence from observational studies seems to indicate that SGLT2i, GLP-1 RA, and DPP4i may be safe and effective for glycemic control in KTR, but their benefit in reducing CV events in this otherwise high-risk population remains unproven. These newer drugs must still be used with care due to the increased propensity of KTR for intravascular volume depletion and acute kidney injury due to diarrhea and their single-kidney status, pre-existing burden of peripheral vascular disease, urinary tract infections due to immunosuppression and a surgically altered urinary tract, erythrocytosis from calcineurin inhibitors, and reduced kidney function from acute or chronic rejection.
Collapse
Affiliation(s)
- Tess Montada-Atin
- Kidney Transplant Program, St. Michael's Hospital, Toronto M5C 2T2, Ontario, Canada
| | - G V Ramesh Prasad
- Kidney Transplant Program, St. Michael's Hospital, Toronto M5C 2T2, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto M5C 2T2, Canada
| |
Collapse
|
|
44
|
Bhat M, Usmani SE, Azhie A, Woo M. Metabolic Consequences of Solid Organ Transplantation. Endocr Rev 2021; 42:171-197. [PMID: 33247713 DOI: 10.1210/endrev/bnaa030] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Indexed: 12/12/2022]
Abstract
Metabolic complications affect over 50% of solid organ transplant recipients. These include posttransplant diabetes, nonalcoholic fatty liver disease, dyslipidemia, and obesity. Preexisting metabolic disease is further exacerbated with immunosuppression and posttransplant weight gain. Patients transition from a state of cachexia induced by end-organ disease to a pro-anabolic state after transplant due to weight gain, sedentary lifestyle, and suboptimal dietary habits in the setting of immunosuppression. Specific immunosuppressants have different metabolic effects, although all the foundation/maintenance immunosuppressants (calcineurin inhibitors, mTOR inhibitors) increase the risk of metabolic disease. In this comprehensive review, we summarize the emerging knowledge of the molecular pathogenesis of these different metabolic complications, and the potential genetic contribution (recipient +/- donor) to these conditions. These metabolic complications impact both graft and patient survival, particularly increasing the risk of cardiovascular and cancer-associated mortality. The current evidence for prevention and therapeutic management of posttransplant metabolic conditions is provided while highlighting gaps for future avenues in translational research.
Collapse
Affiliation(s)
- Mamatha Bhat
- Multi Organ Transplant program and Division of Gastroenterology & Hepatology, University Health Network, Ontario M5G 2N2, Department of Medicine, University of Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Shirine E Usmani
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Ontario, and Sinai Health System, Ontario, University of Toronto, Toronto, Ontario, Canada
| | - Amirhossein Azhie
- Multi Organ Transplant program and Division of Gastroenterology & Hepatology, University Health Network, Ontario M5G 2N2, Department of Medicine, University of Toronto, Ontario, Canada.,Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Minna Woo
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada.,Division of Endocrinology and Metabolism, Department of Medicine, University Health Network, Ontario, and Sinai Health System, Ontario, University of Toronto, Toronto, Ontario, Canada
| |
Collapse
|
|
45
|
Sanyal D, Biswas M, Chaudhari N. Long-term efficacy and safety of anti-hyperglycaemic agents in new-onset diabetes after transplant: Results from outpatient-based 1-year follow-up and a brief review of treatment options. Diabetes Metab Syndr 2021; 15:13-19. [PMID: 33278690 DOI: 10.1016/j.dsx.2020.11.019] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 10/14/2020] [Accepted: 11/20/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND AND AIMS Evaluation of long-term efficacy and safety of various anti-hyperglycaemic agents (AHA) for glycaemic control in NODAT, in stable kidney transplant recipients (KTRs) during 1-year outpatient follow-up. METHODS We collected FPG, PPG, HbA1c, serum creatinine, eGFR, blood tacrolimus level, hypoglycaemia and body weight values from an existing database of KTRs diagnosed to have NODAT. Those newly initiated on AHA over 3 months post-transplant; received standard triple immunosuppressive therapy; and followed up for 1-year after referral, were included. RESULTS In ninety-five patients' (Male = 65), mean decrease at 1-year from baseline in FPG (185.01 ± 62.11 mg/dL), PPG (293.21 ± 85.23 mg/dL) and HbA1c (8.48 ± 1.08%) was 67.09, 126.11 and 1.4 respectively (p < 0.0001). At 1-year, mean HbA1c was 7.08 ± 0.38%, ninety-one patients achieving HbA1c ≤ 7.5%. Fifty-two patients received oral combination therapy based on linagliptin/metformin/repaglinide/gliclazide, 19 received insulin-based regimen, and 24 received linagliptin monotharapey. Thirty patients reported hypoglycaemia (10 with gliclazide and 15 with insulin) and fifty patients gained body-weight at 1-year. Mean serum creatinine and eGFR significantly improved by 0.29 and 15.77 from baseline of 1.56 ± 0.62 mg/dL and 53.95 ± 16.10 mL/min/1.73 m2 respectively. CONCLUSIONS Significant proportion of NODAT patients achieved long-term glycemic control with improved renal function. Combination therapy was needed in most within 1-year. Linagliptin monotherapy was effective, without producing hypoglycaemia or weight gain.
Collapse
Affiliation(s)
- Debmalya Sanyal
- Department of Endocrinology, KPC Medical College and Hospital, RN Tagore International Institute of Cardiac Sciences, Kolkata, India.
| | - Mansij Biswas
- Department of Medical Affairs, Boehringer Ingelheim, Mumbai, India
| | - Nayan Chaudhari
- Department of Clinical Pharmacology, Seth GS Medical College and KEM Hospital, Mumbai, India
| |
Collapse
|
|
46
|
Hecking M, Sharif A, Eller K, Jenssen T. Management of post-transplant diabetes: immunosuppression, early prevention, and novel antidiabetics. Transpl Int 2021; 34:27-48. [PMID: 33135259 PMCID: PMC7839745 DOI: 10.1111/tri.13783] [Citation(s) in RCA: 73] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2020] [Revised: 08/20/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Post-transplant diabetes mellitus (PTDM) shows a relationship with risk factors including obesity and tacrolimus-based immunosuppression, which decreases pancreatic insulin secretion. Several of the sodium-glucose-linked transporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-RAs) dramatically improve outcomes of individuals with type 2 diabetes with and without chronic kidney disease, which is, as heart failure and atherosclerotic cardiovascular disease, differentially affected by both drug classes (presumably). Here, we discuss SGLT2is and GLP1-RAs in context with other PTDM management strategies, including modification of immunosuppression, active lifestyle intervention, and early postoperative insulin administration. We also review recent studies with SGLT2is in PTDM, reporting their safety and antihyperglycemic efficacy, which is moderate to low, depending on kidney function. Finally, we reference retrospective case reports with GLP1-RAs that have not brought forth major concerns, likely indicating that GLP1-RAs are ideal for PTDM patients suffering from obesity. Although our article encompasses PTDM after solid organ transplantation in general, data from kidney transplant recipients constitute the largest proportion. The PTDM research community still requires data that treating and preventing PTDM will improve clinical conditions beyond hyperglycemia. We therefore suggest that it is time to collaborate, in testing novel antidiabetics among patients of all transplant disciplines.
Collapse
Affiliation(s)
- Manfred Hecking
- Department of Internal Medicine IIIClinical Division of Nephrology & DialysisMedical University of ViennaViennaAustria
| | - Adnan Sharif
- Department of Nephrology and TransplantationQueen Elizabeth HospitalBirminghamUK
| | - Kathrin Eller
- Clinical Division of NephrologyMedical University of GrazGrazAustria
| | - Trond Jenssen
- Department of Organ TransplantationOslo University HospitalRikshospitaletOsloNorway
| |
Collapse
|
|
47
|
Abstract
Post-transplant diabetes mellitus (PTDM) is common following solid organ transplantation, and is a risk factor for graft failure and patient mortality. In addition to standard diabetes risk factors such as obesity and ethnicity, patients undergoing transplantation also have the additional risk factors of immunosuppressive agents and infections such as hepatitis C. Patients undergoing transplant assessment should be screened for diabetes. If non-diabetic, but deemed at high risk, they should be offered careful lifestyle advice to reduce risk of post-transplant weight gain and therefore reduce risk of PTDM. Hyperglycaemia in the early post-operative period should be managed ideally with insulin therapy. Once clinically stable, there may be an opportunity to reduce or stop insulin, and consider oral hypoglycaemic agents. Despite lack of evidence from randomised trials, PTDM should be actively screened for in all transplant recipients, and actively managed with structured education, screening for complications, cardiovascular risk reduction and anti-hyperglycaemic therapy.
Collapse
|
|
48
|
Anderson S, Cotiguala L, Tischer S, Park JM, McMurry K. Review of Newer Antidiabetic Agents for Diabetes Management in Kidney Transplant Recipients. Ann Pharmacother 2020; 55:496-508. [PMID: 32795145 DOI: 10.1177/1060028020951955] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
OBJECTIVE This systematic review describes the efficacy, safety, and drug interactions of dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RAs), and sodium-glucose transport protein 2 (SGLT2) inhibitors in kidney transplant recipients (KTRs). DATA SOURCES Articles were identified by English-language MEDLINE search, published prior to May 2020, using the terms kidney transplant, OR PTDM, OR NODAT, AND metformin, OR DPP4, OR GLP1, OR SGLT2. STUDY SELECTION AND DATA EXTRACTION All selected studies were included if the study population was composed of adult KTRs who were diagnosed with either impaired glucose tolerance, diabetes mellitus (DM), new-onset diabetes after transplant (NODAT), or posttransplantation diabetes mellitus (PTDM). DATA SYNTHESIS In KTRs, there is evidence for safety with DPP-4 inhibitors, GLP-1 RAs, and SGLT2 inhibitors. However, urinary tract infections and a slight initial decrease in renal function may limit use of SGLT2 inhibitors. As compared with the nontransplant type 2 DM population, SGLT2 inhibitors are not as efficacious in KTRs. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE This review provides an overview of the current literature on newer antidiabetic agents, addressing efficacy, safety, and drug interactions to help guide clinical decision-making for their use in KTRs. CONCLUSION Newer antidiabetic agents have been recommended by the American Diabetes Association for potential cardiovascular, renal, and hypoglycemic benefits. Particular agents, such as DPP-4 inhibitors and GLP-1 RAs may play a role in correcting PTDM-related defects. Clinicians need to take into account both patient-specific and drug-specific characteristics when initiating these agents in KTRs.
Collapse
|
|
49
|
Singh P, Taufeeq M, Pesavento TE, Washburn K, Walsh D, Meng S. Comparison of the glucagon-like-peptide-1 receptor agonists dulaglutide and liraglutide for the management of diabetes in solid organ transplant: A retrospective study. Diabetes Obes Metab 2020; 22:879-884. [PMID: 31943645 PMCID: PMC9292640 DOI: 10.1111/dom.13964] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/26/2019] [Accepted: 01/08/2020] [Indexed: 12/28/2022]
Abstract
Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are gaining popularity in the management of diabetes in solid organ transplant (SOT) recipients. There are no studies available comparing the two GLP-1RAs dulaglutide and liraglutide in SOT. We performed a retrospective chart review to assess the safety and effectiveness of these agents in adult SOT with diabetes at 6, 12 and 24 months. There were 63 and 25 recipients on dulaglutide and liraglutide, respectively. There was a sustained reduction in primary endpoints of weight, BMI and insulin requirement with dulaglutide when compared to liraglutide. Decrease in weight was 2%, 4% and 5.2% with dulaglutide and 0.09%, 0.87% and 0.89% with liraglutide at 6, 12 and 24 months respectively. BMI reduction followed the same trend in the two groups. The percentage reduction for insulin was 26% with dulaglutide and 3.6% with liraglutide. There was a 10% reduction in creatinine and a 15% increase in estimated glomerular filtration rate (eGFR) at the end of 24 months with dulaglutide. However, there was an increase in creatinine by 7% and an 8% decrease in eGFR at the end of 24 months with liraglutide.
Collapse
Affiliation(s)
| | - Maryam Taufeeq
- Comprehensive Transplant Centre, Ohio State UniversityColumbus
| | | | | | - Debbie Walsh
- Comprehensive Transplant Centre, Ohio State UniversityColumbus
| | - Shumei Meng
- Comprehensive Transplant Centre, Ohio State UniversityColumbus
| |
Collapse
|
|
50
|
Thangavelu T, Lyden E, Shivaswamy V. A Retrospective Study of Glucagon-Like Peptide 1 Receptor Agonists for the Management of Diabetes After Transplantation. Diabetes Ther 2020; 11:987-994. [PMID: 32072430 PMCID: PMC7136376 DOI: 10.1007/s13300-020-00786-1] [Citation(s) in RCA: 45] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2019] [Indexed: 12/16/2022] Open
Abstract
INTRODUCTION Management of post-transplant diabetes mellitus is challenging; there is a lack of prospective randomized controlled trials for safety and efficacy of antidiabetic medications in solid organ recipients. Glucagon-like peptide 1 receptor agonists (GLP-1RA) are a relatively new class of medications used to manage type 2 diabetes in the general population. They have several benefits besides glycemic control, including weight loss and improved cardiovascular risk. However, they have not been studied extensively in the post-transplant population for safety and efficacy. METHODS We conducted a retrospective study of patients who had received kidney, liver, or heart transplant, had diabetes either pre- or post-transplant, and were treated with GLP-1RA. We identified seven kidney, seven liver, and five heart transplant recipients who had received GLP-1RA. We assessed changes in immunosuppressant levels, rejection episodes, changes in hemoglobin A1c (HbA1c), weight, and body mass index (BMI) while on the GLP-1RA. We also looked at changes in insulin dose, other diabetes medications, heart rate, blood pressure, and renal function. RESULTS After a mean follow-up period of 12 months, there were no significant changes in tacrolimus (FK506) levels and renal function for the period of GLP-1RA use. At the end of 12 months, the mean drop in weight was 4.86 kg [95% CI - 7.79, - 1.93]. The BMI decreased by a mean of 1.63 kg/m2 at the end of 12 months [95% CI - 2.53, - 0.73]. HbA1c decreased from baseline by 1.08% [95% CI - 1.65, - 0.51], 0.96% [95% CI - 1.68, - 0.25], and 0.75% [95% CI - 1.55, 0.05] at 3, 6, and 12 months, respectively. CONCLUSIONS Our data suggest that GLP-1RA do not affect tacrolimus levels or transplant outcomes in solid organ transplant (SOT) recipients in the short term. GLP-1RA also seem to be as effective in SOT recipients for glycemic control and weight loss as in the non-transplant population with diabetes.
Collapse
Affiliation(s)
- Thiyagarajan Thangavelu
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Nebraska Medical Center, Omaha, NE, USA
| | - Elizabeth Lyden
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE, USA
| | - Vijay Shivaswamy
- Division of Diabetes, Endocrinology and Metabolism, Department of Internal Medicine, Nebraska Medical Center, Omaha, NE, USA.
- VA Nebraska, Western Iowa Health Care System, Omaha, NE, USA.
| |
Collapse
|