- Email: [email protected]
Management of Diabetes Mellitus With Glucagonlike Peptide-1 Agonist Liraglutide in Renal Transplant Recipients: A Retrospective Study
Management of Diabetes Mellitus With Glucagonlike Peptide-1 Agonist Liraglutide in Renal Transplant Recipients: A Retrospective Study J.-H. Lioua, Y.-M. Liua, and C.-H. Chenb,c,d,e,* a Department of Pharmacy, bDivision of Basic Medical Sciences, Department of Medical Research, cDivision of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan; dDepartment of Life Science, Tunghai University, Taichung, Taiwan; and eSchool of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
ABSTRACT Background. Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) in Taiwan. Despite the use of steroids and/or calcineurin inhibitors (CNIs) in renal transplantation (RTx), additional challenges occur when a patient displays persisting metabolic disease, carries on an unhealthy lifestyle, or experiences genetic effects. Although RTx recipients could get better glycemic control by oral anti-diabetic drugs (OADs) or several insulin agents, they still need more than two kinds of medication. Liraglutide, a GLP-1 receptor agonist, stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. In addition, it delays gastric emptying and suppresses appetite through the central pathways. Herein we report on the long-term benefits of liraglutide in the management of DM in RTx recipients. Methods. We retrospectively retrieved 7 RTx patients in August 2015, who had been prescribed liraglutide due to their poor glycemic control; however, 2 of them discontinued their scheduled doses within 1 month. The mean follow-up period was 19.4 7.6 (range 10.5e27.6) months. Results. Glycemic control improved fasting blood sugar (FBS) from an initial 228.6 39.1 mg/dL to a final FBS of 166.0 26.6 mg/dL (P ¼ .103), with a significant improvement in nadir glucose control (136.4 5.8 mg/dL, P ¼ .017) and with glycated hemoglobin (HbA1c) from an initial 10.0 1.6% to a final 8.1 0.8% (P ¼ .043). The average body weight was from an initial of 78.0 7.8 kg to a nadir of 75.1 9.1 kg (P ¼ .032). Graft renal function of the estimated glomerular filtration rate (eGFR) significantly improved from an initial 67.7 18.7 to a nadir of eGFR 76.5 18.7 mg/dL (P ¼ .024). There was no significant change in urinary protein:creatinine ratio. Conclusion. Liraglutide may be safe and effective for RTx recipients with poor diabetic glycemic control, although there have been incidences of intolerance in some patients, and potential concern regarding absorption of oral medications due to a delay of gastric emptying. Evidence of liraglutide in diabetic RTx recipients is limited, so additional prospective clinical studies should be undertaken in the future.
This study was supported by a grant from Taichung Veterans General Hospital (TCVGH-1077302B and TCVGH-1077302B), Taichung, Taiwan.
0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.03.087
2502
*Address correspondence to Cheng-Hsu Chen, MD, PhD, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung 40705, Taiwan. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 2502e2505 (2018)
TREATING DM WITH GLP-1 AGONIST
D
IABETES Mellitus (DM) is the major cause (45%) of end-stage renal disease (ESRD) in Taiwan [1]. It becomes even more of a challenge after renal transplantation (RTx) when steroids and/or calcineurin inhibitors (CNIs) are administered. Additional challenges occur when a patient displays persisting metabolic disease, carries on an unhealthy lifestyle, or experiences genetic effects. Although there are several insulin and noninsulin agents that could offer better glycemic control than those administered previously, there are still patients who have been prescribed more than 2 kinds of medication [2]. Liraglutide, a GLP-1 receptor agonist, stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. In addition, it also delays gastric emptying and suppresses appetite through the central pathways. Although it may provide the benefit of reducing body weight (BW) and offer better sugar control after RTx, there remains concern about its potential for affecting the therapeutic level of the immunosuppressive agents, such as CNIs, when using liraglutide after RTx [3e5]. Herein we report on the long-term benefits and safety of liraglutide in the management of DM in RTx recipients. MATERIALS AND METHODS We retrospectively retrieved 7 RTx patients in August 2015, who had been prescribed liraglutide with initial dose of 0.6 mg/day for 1 week adjusted every 0.6 mg weekly to optimal glycemic response upto maximal dose 1.8 mg/day due to poor glycemic control; however, 2 of them (28.6%) discontinued their scheduled doses within 1 month. One had nausea and vomiting, whereas the other had uncontrollable headaches, dizziness, and rhinorrhea. The initial renal function data were determined with serum creatinine (sCr) 1.21 0.44 mg/dL (range 0.76e2.03 mg/dL), estimated glomerular filtration rate (eGFR) was 67.66 18.69 mL/min (range 38.29e92.59 mL/min), and glucose (Glu) was 228.6 39.1 mg/dL (range 161e281 mg/dL) with glycated hemoglobin (HbA1c) 10.04 1.61% (range 8.1%-12.1%). The initial blood glucose control included different combinations with 2 patients (40%) on insulin, 4 (80%) on metformin, 3 (60%) on sulfonylurea, 2 (40%) on alpha-glucosidase inhibitor, and 3 (60%) on dipeptidylpeptidase-4 (DPP-4) inhibitor. Liraglutide was added on from an initial 0.6-mg dose once daily for 1 week. Its dose was then adjusted weekly according to suggestions made by the American Diabetes Association (ADA) for blood sugar control [6], until the maximum dose of 1.8 mg once daily was reached. The insulin was discontinued and oral antidiabetic drugs (OADs) were adjusted by sugar control. The mean follow-up period was 19.4 7.6 (range 10.5e27.6) months.
RESULTS Benefits of Liraglutide in Diabetic RTx Recipients
The addition of liraglutide in diabetic RTx recipients improved sugar control through fasting blood sugar and HbA1c. It allowed for better graft renal function (Table 1). Although 4 patients (80%) had body weight (BW) reduction (range -2.1 to -3.0 kg) over a span of 10.5e27.6 months, 1 gained 8 kg during the management period of 17.3 months without a significant difference in BW control after
2503 Table 1. Clinical Outcomes of Diabetic RTx Recipients After Administration of Liraglutide Before
Body weight (kg) Nadir body weight (kg) Body mass index (kg/m2) Cr (mg/dL) Nadir creatinine (mg/dL) eGFR (mL/min) Best eGFR (mL/min) Protein/Cr ratio Nadir protein/Cr ratio Glucose (mg/dL) Nadir glucose (mg/dL) HbA1c (%) Nadir HbA1c (%) Dose of liraglutide (mg) OAD pill numbers
78.0 7.8 29.4 2.8 1.21 0.44 67.66 18.69 1.38 1.67 228.6 39.1 10.04 1.61 0.6 0.0 4.6 2.7
After
P
.922 .032* .923 .245 .044* .136 .024* .181 .173 .103 .017* .047* .031* .033* .282
77.7 75.1 29.5 1.14 1.07 73.86 76.53 0.604 0.55 166 136.4 8.14 7.76 1.3 3.0
12.3 9.1 4.1 0.49 0.37 20.23 18.69 0.72 0.67 26.6 19.6 0.83 0.7 0.5 1.3
Abbreviations: Cr, creatinine; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; RTx, renal transplantation. *Statistically significant.
liraglutide. The nadir BW (75.1 9.1 kg) was a significant reduction from baseline BW (78.0 7.8 kg; P ¼ .032). Two patients discontinued insulin injections (1 premixed and 1 basal insulin), whereas most could decrease their OAD burden (4.6 2.7 vs 3.0 1.3), although no statistically significant difference was observed (P ¼ .282). Safety and Adverse Events
Due to the possibility that GLP-1 may delay gastric emptying and potentially interfere with medication absorption, our regular therapeutic drug monitoring (TDM) regarding trough levels of tacrolimus disclosed their steadystate concentration, where 3 of 5 RTx recipients could reduce their dose of tacrolimus and maintain an optimal therapeutic level (Fig 1). The patients had no episodes of hypoglycemia, nor any serious adverse events related to GLP-1 therapy, although mild symptoms, including nausea, a reduced appetite, headaches, injection-site pain, and weakness, were temporarily reported without any initial complications. DISCUSSION
ESRD patients nearly always recover their health and go on to experience a full life expectancy, along with a better quality of life after successful RTx. However, these patients continue to have higher morbidity and mortality rates (and their underlying diseases, particularly DM) than those in the general population, while also requiring long-term use of immunosuppressive agents. Chronic hyperglycemia has a detrimental cardiovascular effect as it triggers inflammatory responses and oxidative stress resulting in a vicious cycle involving impaired insulin sensitivity, b-cell loss, and endothelial dysfunction, all of which can lead to micro- and macrovascular complications [7]. Diabetic control has been shown
2504
LIOU, LIU, AND CHEN
Fig 1. Trough level (A) and dose (B) of tacrolimus after the administration of liraglutide.
to reduce major cardiovascular events in most published trials, but severe hypoglycemia may increase cardiovascular mortality. There is growing evidence-based importance regarding different glucose-control medications in cardiovascular outcomes, as some studies have suggested adverse cardiovascular effects due to sulfonylureas, insulin, and thiazolidinediones. Meta-analyses of available trials have also shown significant reductions in cardiovascular morbidity after treatment with DPP-4 and GLP-1 [7e9]. The most significant of these studies involved renal outcomes associated with the LEADER trial, which showed that liraglutide decreased the
development and progression of diabetic kidney disease when compared with placebo [10]. Liraglutide, an incretin mimetic that stimulates insulin secretion, inhibits glucagon synthesis and prolongs gastric emptying. In addition, it displays a b-cell‒protective effect from glucocorticoids [11], while also preventing toxicity of CNIs in vitro [12]. Accordingly, our study had 2 RTx recipients who discontinued liraglutide due to the aforementioned symptoms, with the other 5 recipients having only initial mild symptoms. We assured these patients we would monitor/handle their gastrointestinal symptoms soon after
TREATING DM WITH GLP-1 AGONIST
starting administration, as we gradually titrated according to sugar control. Pinelli et al reported that liraglutide did not alter short-term trough tacrolimus levels in RTx recipients clinically [13], whereas our data show that it may be safe and effective to improve glycemic management in poor diabetic control RTx recipients. This result diminished any concern regarding interference of drug absorption via delayed gastric emptying. Evidence of liraglutide’s positive effects in diabetic RTx recipients remains limited, and therefore additional prospective clinical studies should be performed. REFERENCES [1] 2015 Annual Report on Kidney Disease in Taiwan. http://www. tsn.org.tw/UI/L/TWRD/ebook_2017%E5%B9%B4%E5%A0%B1.pdf [2] Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016;316:313e24. [3] Pérez-Sáez MJ, Marín-Casino M, Pascual J. Treating post transplantation diabetes mellitus. Expert Opin Pharmacother 2015;16:1435e48. [4] Shivaswamy V, Boerner B, Larsen J. Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes. Endocr Rev 2016;37:37e61.
2505 [5] Sharif A, Cohney S. Post-transplantation diabetesdstate of the art. Lancet Diabetes Endocrinol 2016;4:337e49. [6] American Diabetes Association 13. Diabetes care in the hospital, nursing home, and skilled nursing facility. Diabetes Care 2015;38(suppl 1):S80e5. [7] Mannucci E, Dicembrini I, Lauria A, Pozzilli P. Is glucose control important for prevention of cardiovascular disease in diabetes? Diabetes Care 2013;36(suppl 2):S259e63. [8] Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112e20. [9] Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a metaanalysis. Lancet Diabetes Endocrinol 2018;6:105e13. [10] Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839e48. [11] Werzowa J, Hecking M, Haidinger M, Lechner F, Döller D, Pacini G, et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation a randomized, placebo-controlled clinical trial. Transplantation 2013;95:456e62. [12] D’Amico E, Hui H, Khoury N, Di Mario U, Perfetti R. Pancreatic beta-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs. J Mol Endocrinol 2005;34:377e90. [13] Pinelli NR, Patel A, Salinitri FD. Co-administration of liraglutide with tacrolimus in kidney transplant recipients: a case series. Diabetes Care 2013;36:e171e2.
ABSTRACT Background. Diabetes mellitus (DM) is the major cause of end-stage renal disease (ESRD) in Taiwan. Despite the use of steroids and/or calcineurin inhibitors (CNIs) in renal transplantation (RTx), additional challenges occur when a patient displays persisting metabolic disease, carries on an unhealthy lifestyle, or experiences genetic effects. Although RTx recipients could get better glycemic control by oral anti-diabetic drugs (OADs) or several insulin agents, they still need more than two kinds of medication. Liraglutide, a GLP-1 receptor agonist, stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. In addition, it delays gastric emptying and suppresses appetite through the central pathways. Herein we report on the long-term benefits of liraglutide in the management of DM in RTx recipients. Methods. We retrospectively retrieved 7 RTx patients in August 2015, who had been prescribed liraglutide due to their poor glycemic control; however, 2 of them discontinued their scheduled doses within 1 month. The mean follow-up period was 19.4 7.6 (range 10.5e27.6) months. Results. Glycemic control improved fasting blood sugar (FBS) from an initial 228.6 39.1 mg/dL to a final FBS of 166.0 26.6 mg/dL (P ¼ .103), with a significant improvement in nadir glucose control (136.4 5.8 mg/dL, P ¼ .017) and with glycated hemoglobin (HbA1c) from an initial 10.0 1.6% to a final 8.1 0.8% (P ¼ .043). The average body weight was from an initial of 78.0 7.8 kg to a nadir of 75.1 9.1 kg (P ¼ .032). Graft renal function of the estimated glomerular filtration rate (eGFR) significantly improved from an initial 67.7 18.7 to a nadir of eGFR 76.5 18.7 mg/dL (P ¼ .024). There was no significant change in urinary protein:creatinine ratio. Conclusion. Liraglutide may be safe and effective for RTx recipients with poor diabetic glycemic control, although there have been incidences of intolerance in some patients, and potential concern regarding absorption of oral medications due to a delay of gastric emptying. Evidence of liraglutide in diabetic RTx recipients is limited, so additional prospective clinical studies should be undertaken in the future.
This study was supported by a grant from Taichung Veterans General Hospital (TCVGH-1077302B and TCVGH-1077302B), Taichung, Taiwan.
0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.03.087
2502
*Address correspondence to Cheng-Hsu Chen, MD, PhD, Division of Nephrology, Department of Internal Medicine, Taichung Veterans General Hospital, 1650 Taiwan Boulevard Section 4, Taichung 40705, Taiwan. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 2502e2505 (2018)
TREATING DM WITH GLP-1 AGONIST
D
IABETES Mellitus (DM) is the major cause (45%) of end-stage renal disease (ESRD) in Taiwan [1]. It becomes even more of a challenge after renal transplantation (RTx) when steroids and/or calcineurin inhibitors (CNIs) are administered. Additional challenges occur when a patient displays persisting metabolic disease, carries on an unhealthy lifestyle, or experiences genetic effects. Although there are several insulin and noninsulin agents that could offer better glycemic control than those administered previously, there are still patients who have been prescribed more than 2 kinds of medication [2]. Liraglutide, a GLP-1 receptor agonist, stimulates insulin secretion and inhibits glucagon secretion and hepatic glucose production in a glucose-dependent manner. In addition, it also delays gastric emptying and suppresses appetite through the central pathways. Although it may provide the benefit of reducing body weight (BW) and offer better sugar control after RTx, there remains concern about its potential for affecting the therapeutic level of the immunosuppressive agents, such as CNIs, when using liraglutide after RTx [3e5]. Herein we report on the long-term benefits and safety of liraglutide in the management of DM in RTx recipients. MATERIALS AND METHODS We retrospectively retrieved 7 RTx patients in August 2015, who had been prescribed liraglutide with initial dose of 0.6 mg/day for 1 week adjusted every 0.6 mg weekly to optimal glycemic response upto maximal dose 1.8 mg/day due to poor glycemic control; however, 2 of them (28.6%) discontinued their scheduled doses within 1 month. One had nausea and vomiting, whereas the other had uncontrollable headaches, dizziness, and rhinorrhea. The initial renal function data were determined with serum creatinine (sCr) 1.21 0.44 mg/dL (range 0.76e2.03 mg/dL), estimated glomerular filtration rate (eGFR) was 67.66 18.69 mL/min (range 38.29e92.59 mL/min), and glucose (Glu) was 228.6 39.1 mg/dL (range 161e281 mg/dL) with glycated hemoglobin (HbA1c) 10.04 1.61% (range 8.1%-12.1%). The initial blood glucose control included different combinations with 2 patients (40%) on insulin, 4 (80%) on metformin, 3 (60%) on sulfonylurea, 2 (40%) on alpha-glucosidase inhibitor, and 3 (60%) on dipeptidylpeptidase-4 (DPP-4) inhibitor. Liraglutide was added on from an initial 0.6-mg dose once daily for 1 week. Its dose was then adjusted weekly according to suggestions made by the American Diabetes Association (ADA) for blood sugar control [6], until the maximum dose of 1.8 mg once daily was reached. The insulin was discontinued and oral antidiabetic drugs (OADs) were adjusted by sugar control. The mean follow-up period was 19.4 7.6 (range 10.5e27.6) months.
RESULTS Benefits of Liraglutide in Diabetic RTx Recipients
The addition of liraglutide in diabetic RTx recipients improved sugar control through fasting blood sugar and HbA1c. It allowed for better graft renal function (Table 1). Although 4 patients (80%) had body weight (BW) reduction (range -2.1 to -3.0 kg) over a span of 10.5e27.6 months, 1 gained 8 kg during the management period of 17.3 months without a significant difference in BW control after
2503 Table 1. Clinical Outcomes of Diabetic RTx Recipients After Administration of Liraglutide Before
Body weight (kg) Nadir body weight (kg) Body mass index (kg/m2) Cr (mg/dL) Nadir creatinine (mg/dL) eGFR (mL/min) Best eGFR (mL/min) Protein/Cr ratio Nadir protein/Cr ratio Glucose (mg/dL) Nadir glucose (mg/dL) HbA1c (%) Nadir HbA1c (%) Dose of liraglutide (mg) OAD pill numbers
78.0 7.8 29.4 2.8 1.21 0.44 67.66 18.69 1.38 1.67 228.6 39.1 10.04 1.61 0.6 0.0 4.6 2.7
After
P
.922 .032* .923 .245 .044* .136 .024* .181 .173 .103 .017* .047* .031* .033* .282
77.7 75.1 29.5 1.14 1.07 73.86 76.53 0.604 0.55 166 136.4 8.14 7.76 1.3 3.0
12.3 9.1 4.1 0.49 0.37 20.23 18.69 0.72 0.67 26.6 19.6 0.83 0.7 0.5 1.3
Abbreviations: Cr, creatinine; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; OAD, oral antidiabetic drug; RTx, renal transplantation. *Statistically significant.
liraglutide. The nadir BW (75.1 9.1 kg) was a significant reduction from baseline BW (78.0 7.8 kg; P ¼ .032). Two patients discontinued insulin injections (1 premixed and 1 basal insulin), whereas most could decrease their OAD burden (4.6 2.7 vs 3.0 1.3), although no statistically significant difference was observed (P ¼ .282). Safety and Adverse Events
Due to the possibility that GLP-1 may delay gastric emptying and potentially interfere with medication absorption, our regular therapeutic drug monitoring (TDM) regarding trough levels of tacrolimus disclosed their steadystate concentration, where 3 of 5 RTx recipients could reduce their dose of tacrolimus and maintain an optimal therapeutic level (Fig 1). The patients had no episodes of hypoglycemia, nor any serious adverse events related to GLP-1 therapy, although mild symptoms, including nausea, a reduced appetite, headaches, injection-site pain, and weakness, were temporarily reported without any initial complications. DISCUSSION
ESRD patients nearly always recover their health and go on to experience a full life expectancy, along with a better quality of life after successful RTx. However, these patients continue to have higher morbidity and mortality rates (and their underlying diseases, particularly DM) than those in the general population, while also requiring long-term use of immunosuppressive agents. Chronic hyperglycemia has a detrimental cardiovascular effect as it triggers inflammatory responses and oxidative stress resulting in a vicious cycle involving impaired insulin sensitivity, b-cell loss, and endothelial dysfunction, all of which can lead to micro- and macrovascular complications [7]. Diabetic control has been shown
2504
LIOU, LIU, AND CHEN
Fig 1. Trough level (A) and dose (B) of tacrolimus after the administration of liraglutide.
to reduce major cardiovascular events in most published trials, but severe hypoglycemia may increase cardiovascular mortality. There is growing evidence-based importance regarding different glucose-control medications in cardiovascular outcomes, as some studies have suggested adverse cardiovascular effects due to sulfonylureas, insulin, and thiazolidinediones. Meta-analyses of available trials have also shown significant reductions in cardiovascular morbidity after treatment with DPP-4 and GLP-1 [7e9]. The most significant of these studies involved renal outcomes associated with the LEADER trial, which showed that liraglutide decreased the
development and progression of diabetic kidney disease when compared with placebo [10]. Liraglutide, an incretin mimetic that stimulates insulin secretion, inhibits glucagon synthesis and prolongs gastric emptying. In addition, it displays a b-cell‒protective effect from glucocorticoids [11], while also preventing toxicity of CNIs in vitro [12]. Accordingly, our study had 2 RTx recipients who discontinued liraglutide due to the aforementioned symptoms, with the other 5 recipients having only initial mild symptoms. We assured these patients we would monitor/handle their gastrointestinal symptoms soon after
TREATING DM WITH GLP-1 AGONIST
starting administration, as we gradually titrated according to sugar control. Pinelli et al reported that liraglutide did not alter short-term trough tacrolimus levels in RTx recipients clinically [13], whereas our data show that it may be safe and effective to improve glycemic management in poor diabetic control RTx recipients. This result diminished any concern regarding interference of drug absorption via delayed gastric emptying. Evidence of liraglutide’s positive effects in diabetic RTx recipients remains limited, and therefore additional prospective clinical studies should be performed. REFERENCES [1] 2015 Annual Report on Kidney Disease in Taiwan. http://www. tsn.org.tw/UI/L/TWRD/ebook_2017%E5%B9%B4%E5%A0%B1.pdf [2] Palmer SC, Mavridis D, Nicolucci A, Johnson DW, Tonelli M, Craig JC, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA 2016;316:313e24. [3] Pérez-Sáez MJ, Marín-Casino M, Pascual J. Treating post transplantation diabetes mellitus. Expert Opin Pharmacother 2015;16:1435e48. [4] Shivaswamy V, Boerner B, Larsen J. Post-transplant diabetes mellitus: causes, treatment, and impact on outcomes. Endocr Rev 2016;37:37e61.
2505 [5] Sharif A, Cohney S. Post-transplantation diabetesdstate of the art. Lancet Diabetes Endocrinol 2016;4:337e49. [6] American Diabetes Association 13. Diabetes care in the hospital, nursing home, and skilled nursing facility. Diabetes Care 2015;38(suppl 1):S80e5. [7] Mannucci E, Dicembrini I, Lauria A, Pozzilli P. Is glucose control important for prevention of cardiovascular disease in diabetes? Diabetes Care 2013;36(suppl 2):S259e63. [8] Monami M, Ahrén B, Dicembrini I, Mannucci E. Dipeptidyl peptidase-4 inhibitors and cardiovascular risk: a meta-analysis of randomized clinical trials. Diabetes Obes Metab 2013;15:112e20. [9] Bethel MA, Patel RA, Merrill P, Lokhnygina Y, Buse JB, Mentz RJ, et al. Cardiovascular outcomes with glucagon-like peptide-1 receptor agonists in patients with type 2 diabetes: a metaanalysis. Lancet Diabetes Endocrinol 2018;6:105e13. [10] Mann JFE, Ørsted DD, Brown-Frandsen K, Marso SP, Poulter NR, Rasmussen S, et al. Liraglutide and renal outcomes in type 2 diabetes. N Engl J Med 2017;377:839e48. [11] Werzowa J, Hecking M, Haidinger M, Lechner F, Döller D, Pacini G, et al. Vildagliptin and pioglitazone in patients with impaired glucose tolerance after kidney transplantation a randomized, placebo-controlled clinical trial. Transplantation 2013;95:456e62. [12] D’Amico E, Hui H, Khoury N, Di Mario U, Perfetti R. Pancreatic beta-cells expressing GLP-1 are resistant to the toxic effects of immunosuppressive drugs. J Mol Endocrinol 2005;34:377e90. [13] Pinelli NR, Patel A, Salinitri FD. Co-administration of liraglutide with tacrolimus in kidney transplant recipients: a case series. Diabetes Care 2013;36:e171e2.