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Post-transplant diabetes mellitus (PTDM) is a frequent complication post-heart transplantation (HT), however long-term prevalence studies are missing. The aim of this study was to determine the prevalence and determinants of PTDM as well as prediabetes long-term post-HT using oral glucose tolerance tests (OGTT). Also, the additional value of OGTT compared to fasting glucose and glycated hemoglobin (HbA1c) was investigated. All patients > 1 year post-HT seen at the outpatient clinic between August 2018 and April 2021 were screened with an OGTT. Patients with known diabetes, an active infection/rejection/malignancy or patients unwilling or unable to undergo OGTT were excluded. In total, 263 patients were screened, 108 were excluded. The included 155 patients had a median age of 54.3 [42.2–64.3] years, and 63 (41%) were female. Median time since HT was 8.5 [4.8–14.5] years. Overall, 51 (33%) had a normal range, 85 (55%) had a prediabetes range and 19 (12%) had a PTDM range test. OGTT identified prediabetes and PTDM in more patients (18% and 50%, respectively), than fasting glucose levels and HbA1c. Age at HT (OR 1.03 (1.00–1.06),
Type 2 diabetes mellitus is an increasing problem worldwide, leading to reduced life expectancy and increased risk for cardiovascular complications (
In solid-organ transplant recipients, the incidences of post-transplant diabetes mellitus (PTDM) are high, varying between 10 and 40% depending on the transplanted organ and definitions used (
Recently, data from the ISHLT registry showed that PTDM was associated with an increased risk for severe renal dysfunction, retransplantation and death (
Previous studies in the general population have shown the added value of the oral glucose tolerance test (OGTT) to fasting glucose levels and glycated hemoglobin (HbA1c) for identifying patients with (pre)diabetes, with a significant number of patients being missed without the OGTT (
In the current study, we investigated the prevalence of prediabetes and diabetes mellitus long-term post-HT and determinants for an abnormal OGTT long-term post-HT. Additionally, the added value of an OGTT compared to a fasting glucose and HbA1c is investigated.
In this cross-sectional study, all adult HT patients who were more than 1 year post-HT that were seen at our outpatient clinic between August 2018 and April 2021 were screened to undergo an OGTT. Patients with known diabetes, an active infection/rejection treatment, patients who were treated for a malignancy and patients unwilling or unable to undergo OGTT were excluded. Information on immunosuppressive regimen has been published before (
The OGTT was performed according to the guidelines of de American Diabetes Association (ADA) (
Transient hyperglycemia was defined as a patient needing insulin because of hyperglycemia in the first days post-operatively up until 45 days, based on the consensus document published by Sharif et al. (
The definitions for the results of the OGTTs were according to the ADA guidelines (
Normality of distribution was tested using the Shapiro-Wilks test. Continuous variables were expressed with a mean ± standard deviation (SD) when normally distributed and compared with a student t-test or one-way ANOVA depending on the number of groups. If the data were not normally distributed a median was presented with the 25th—75th percentile (Interquartile range, IQR) and compared using a Mann-Whitney or Kruskal Wallis test. Categorical variables were demonstrated as numbers with percentages (%) and compared with a Chi square or Fisher’s exact test where appropriate. To determine risk factors for an abnormal test result from OGTT (PTDM and prediabetes range tests) a binary logistic regression analysis was performed. First, an univariable analysis was performed including the sex of the recipient and the recipient age at the time of the HT. In order to not overfit the analysis, a propensity score was created which included variables that have been linked to PTDM in the literature. These variables included: ethnicity, time between heart transplantation and OGTT, heart failure etiology, transient hyperglycemia, resolved PTDM, number of rejections (patients with more than 3 rejections included into one group), cytomegalovirus disease, body mass index at time of OGTT, tacrolimus use at time of OGTT, and prednisolone use at time of OGTT. In a multivariable analysis, age, recipient sex and the propensity score were included. Additionally, an ordinal regression analysis was performed. In this analysis, age and a propensity score including all previously mentioned variables and recipient gender were included. A p-value < 0.05 was considered as statistically significant. The data were analyzed with IBM SPSS statistics 25 (IBM Corp., New Orchard Road, Amonk, NY10504, United States).
In total, 263 patients were screened at the outpatient clinic of whom 96 (37%) were female. The median age at HT was 47.1 [32.5–55.0] years old. The etiology of heart failure pre-HT was ischemic cardiomyopathy in 27% of patients; 17% had a left ventricular assist device pre-HT. During the admission directly after HT, 115 (44%) developed transient hyperglycemia. Reversed PTDM was seen in 37 (14%) patients, while 71 (27%) patients had known diabetes mellitus. Other baseline characteristics are demonstrated in
Baseline characteristics all screened patients and divided into groups (patient who underwent oral glucose tolerance test versus those who did not).
Parameters | Whole Cohort | Patient Not Undergoing OGTT | Patients Undergoing OGTT | p-value |
---|---|---|---|---|
Number of patients | 263 | 108 | 155 | |
Female | 96 (37) | 33 (31) | 63 (41) | 0.10 |
Ethnicity | 0.25 | |||
Caucasian | 227 (86) | 89 (82) | 138 (89) | |
Black | 8 (3) | 5 (5) | 3 (2) | |
Other | 28 (11) | 14 (13) | 14 (9) | |
Age at HT (years) | 47.1 [32.5–55.0] | 48.7 [38.1–56.8] | 46.2 [26.1–53.6] | 0.047 |
Age at OGTT (years) | 54.3 [42.2–64.3] | |||
Time HT—OGTT (years) | 8.5 [4.8–14.5] | |||
Etiology heart failure | 0.001 | |||
Ischemic CMP | 70 (27) | 40 (37) | 30 (19) | |
Non-ischemic CMP | 193 (73) | 68 (63) | 125 (81) | |
LVAD pre-HT | 45 (17) | 11 (10) | 34 (22) | 0.01 |
BMI at HT | 23.1 ± 4.5 | 24.0 ± 4.9 | 22.4 ± 4.1 | 0.006 |
BMI at OGTT | 25.8 [23.7–27.7] | |||
Prednisolone use 1 year post-HT | 236 (90) | 102 (94) | 134 (87) | 0.03 |
Medication at OGTT | ||||
Tacrolimus | 140 (90) | |||
Ciclosporin | 15 (10) | |||
Mycophenolate mofetil | 65 (42) | |||
Everolimus | 27 (17) | |||
Prednisolone | 93 (60) | |||
Prednisolone dosage (mg) | 5.0 [5.0–7.5] | |||
Glycemic status | ||||
Transient hyperglycemia post-HT | 115 (44) | 31 (29) | 84 (54) | <0.001 |
Reversed PTDM post-HT | 37 (14) | 7 (6) | 30 (19) | 0.003 |
Known DM at OGTT | 71 (27) | 71 (66) | 0 (0) | <0.001 |
DM pre-HT | 22 (8) | 22 (20) | 0 (0) | |
DM post-HT | 49 (19) | 49 (45) | 0 (0) | |
Rejections |
1 [0–2] | 1 [0–2] | 1 [0–2] | 0.007 |
CMV infection | 53 (20) | 19 (18) | 34 (22) | 0.39 |
Number of rejections treated with methylprednisolone.
Baseline characteristics of all patients and those who underwent oral glucose tolerance test (including patients in whom the diagnosis was determined based on fasting glucose and HbA1c). Continuous variables are demonstrated with mean ± standard deviation when normally distributed and median with [25th—75th percentile] when not normally distributed. Categorical variables are demonstrated with numbers and (%).
Abbreviations: BMI, body mass index; CMP, cardiomyopathy; CMV, cytomegalovirus; DM, diabetes mellitus; HT, heart transplantation; LVAD, left ventricular assist device; OGTT, oral glucose tolerance test.
Results screening and oral glucose tolerance test. Results of screening and oral glucose tolerance test for all patients (
In 148 out of 155 patients an OGTT was performed since in seven patients PTDM could be diagnosed based on solely the fasting glucose level in combination with the HbA1c (
When including the results after 6 weeks to confirm (when needed) the diagnosis of PTDM, based on OGTT 51 (34%) of patients had a normal glucose tolerance, 85 (57%) had a prediabetes range test and 12 (8%) had a PTDM range test. Together with the 7 patients in whom the diagnosis was confirmed using fasting glucose and HbA1c, 51/155 (33%) had a normal range test, 85/155 (55%) had a prediabetes range test and 19/155 (12%) of patients had a diabetes range test during the study period. The baseline characteristics of the patients undergoing OGTT (
Baseline characteristics based on oral glucose tolerance test result.
Results OGTT | ||||
---|---|---|---|---|
Parameters | Normal Range | Prediabetes | PTDM | p-value |
Number of patients | 51 | 85 | 19 | |
Female | 26 (51) | 30 (35) | 7 (37) | 0.18 |
Ethnicity | 0.28 | |||
Caucasian | 47 (92) | 73 (86) | 18 (95) | |
Black | 2 (4) | 1 (1) | 0 (0) | |
Other | 2 (4) | 11 (13) | 1 (5) | |
Age at HT (years) | 38.7 [22.2–52.1] | 49.3 [33.9–55.1] | 45.6 [25.4–50.8] | 0.08 |
Age at OGTT (years) | 49.7 [30.4–56.7] | 57.7 [46.9–66.1] | 54.8 [42.0–65.4] | 0.019 |
Time HT—OGTT (years) | 8.4 [3.5–11.8] | 8.5 [5.1–15.0] | 11.5 [5.2–19.1] | 0.13 |
Etiology heart failure | 0.23 | |||
Ischemic CMP | 6 (12) | 19 (22) | 5 (26) | |
Non-ischemic CMP | 45 (88) | 66 (78) | 14 (74) | |
LVAD pre-HT | 12 (24) | 18 (21) | 3 (16) | 0.78 |
BMI at HT | 22.3 ± 4.7 | 22.4 ± 3.6 | 22.9 ± 4.4 | 0.85 |
BMI at OGTT | 25.1 [23.3–27.1] | 25.9 [24.1–27.6] | 26.7 [23.0–30.6] | 0.56 |
Prednisolone use 1 year post-HT | 42 (82) | 75 (88) | 17 (89) | 0.74 |
Medication at OGTT | ||||
Tacrolimus | 49 (96) | 75 (88) | 16 (84) | 0.21 |
Ciclosporin | 2 (4) | 10 (12) | 3 (16) | 0.21 |
Mycophenolate mofetil | 23 (45) | 35 (41) | 7 (37) | 0.81 |
Everolimus | 6 (12) | 19 (22) | 2 (11) | 0.20 |
Prednisolone | 27 (53) | 50 (59) | 16 (84) | 0.056 |
Prednisolone dosage (mg) | 5 [5–7.5] | 5 [5–7.5] | 7.5 [5–10] | 0.20 |
Glycemic status | ||||
Transient hyperglycemia post-HT | 32 (63) | 46 (54) | 6 (32) | 0.054 |
Reversed PTDM | 6 (12) | 17 (20) | 7 (37) | 0.07 |
Rejections |
1 [0–1] | 1 [0–2] | 1 [0–2] | 0.18 |
CMV infection | 10 (20) | 20 (24) | 4 (21) | 0.86 |
Number of rejections treated with methylprednisolone.
Baseline characteristics of all patients and those who underwent oral glucose tolerance test (including patients in whom the diagnosis was determined based on fasting glucose and HbA1c). Continuous variables are demonstrated with mean ± standard deviation when normally distributed and median with [25th–75th percentile] when not normally distributed. Categorical variables are demonstrated with numbers and (%).
Abbreviations: BMI, body mass index; CMP, cardiomyopathy; CMV, cytomegalovirus; DM, diabetes mellitus; HT, heart transplantation; LVAD, left ventricular assist device; OGTT, oral glucose tolerance test; PTDM, post-transplant diabetes mellitus.
In total, 40 patients (27%) were within 5 years post-HT and 108 (73%) were more than 5 years post-HT. When the results of the OGTTs were stratified according to the time post-transplant, no significant differences were seen in the results (
For the patients who underwent an OGTT, the results of each component of the OGTT (fasting glucose, 2 h postload glucose, and HbA1c) are demonstrated in
Results of oral glucose tolerance test specified by detection method, combination of all the results and with confirmation test after 6 weeks. Abbreviations: HbA1c, glycated hemoglobin; OGTT, oral glucose tolerance test; PLG, postload glucose.
In order to define determinants for an abnormal OGTT, patients with a prediabetes and PTDM range test were combined. Univariable analysis demonstrated that age at HT (OR 1.02 (1.00–1.04),
Logistic regression analysis investigating determinants of an abnormal oral glucose tolerance test result (prediabetes or diabetes range test).
Abnormal OGTT Result | |||
---|---|---|---|
OR (95% CI) | |||
Univariable | Model 1 | Model 2 | |
Age recipient at HT | 1.02 (1.00–1.04) | 1.02 (1.00–1.04) | 1.03 (1.00–1.06) |
P-value | 0.036 | 0.07 | 0.044 |
Female recipient | 0.53 (0.27–1.05) | 0.59 (0.29–1.18) | 0.60 (0.28–1.31) |
P-value | 0.07 | 0.14 | 0.20 |
Univariable analysis of recipient sex and recipient age at heart transplantation individually in the model.
Model 1: Model including sex and age at the time of the heart transplantation of the recipient.
Model 2: Model including sex and age adjusted for the propensity score which included the following parameters: ethnicity, time between heart transplantation and CT scan, heart failure etiology, transient hyperglycemia, resolved PTDM, number of rejections*, cytomegalovirus disease, body mass index at time of OGTT, tacrolimus use at time of OGTT, and prednisolone use at time of OGTT. *Patients with 3 or more rejections were combined into one group due to the small number of patients.
Abbreviations: CI, confidence interval; HT, heart transplantation; OGTT, oral glucose tolerance test; OR, odds ratio.
Ordinal regression analysis investigating determinants of the oral glucose tolerance test results.
Abnormal OGTT result | ||
---|---|---|
OR (95% CI) | ||
Model 1 | Model 2 | |
Age recipient at HT | 1.02 (1.00–1.04) | 1.03 (1.00–1.05) |
P-value | 0.023 | 0.044 |
Model 1: unadjusted
Model 2: Model including age adjusted for the propensity score which included the following parameters: recipient sex, ethnicity, time between heart transplantation and CT scan, heart failure etiology, transient hyperglycemia, resolved PTDM, number of rejections*, cytomegalovirus disease, body mass index at time of OGTT, tacrolimus use at time of OGTT, and prednisolone use at time of OGTT.
*Patients with 3 or more rejections were combined into one group due to the small number of patients. Abbreviations: CI, confidence interval; HT, heart transplantation; OGTT, oral glucose tolerance test; OR, odds ratio.
This study shows that impaired glucose metabolism is highly prevalent in patients long term post-HT. Based on OGTT, 104 of 155 patients without known PTDM (67%) had an abnormal test of whom 85 (55%) had a prediabetes range test, while 19 (12%) had a PTDM range test. When stratified by time since HT (≤ or > 5 years), there was no difference in the test results (
This is the first study investigating the long-term prevalence of prediabetes and diabetes in HT recipients. In the registry from the ISHLT, diabetes mellitus is monitored up until 5 years post-HT, where diabetes status is reported in accordance with the clinical diagnostic guidance in place at the reporting transplant center (
In our study, a total of 55% of patients had a prediabetes range test. It is essential to monitor the glucose metabolism closely in this patient population because of their high cardiovascular risk profile and highly prevalent risk factors such as hypertension, dyslipidemia, renal dysfunction but also the chronic use of steroids (
Age at HT was a significant determinant for an abnormal OGTT. Unfortunately, we were not able to include other determinants of PTDM in the analysis due to the relatively small study population, such as immunosuppressive regimen (prednisolone, tacrolimus), rejections, and CMV infection (
Our study has several limitations. First of all, this is a single-center study which comes with all its limitations such as generalizability. In our study population, around 10% of patients were unable or unwilling to undergo OGTT which could increase the risk for selection bias. Ultimately, this could mean that the numbers in our study underestimate the frequency of prediabetes and PTDM long-term post-HT. Furthermore, most patients in our population were Caucasian which makes it difficult to extrapolate our study results to populations consisting of other ethnicities.
In conclusion, our study demonstrated that both prediabetes and PTDM are frequently observed in patients not known with PTDM long-term post-HT. Age at HT was a determinant for an abnormal OGTT. OGTT is the preferred test to screen for prediabetes and PTDM since it identifies significantly more patients than (fasting) glucose and HbA1c levels alone. Future studies are needed to investigate the impact of prediabetes and PTDM diagnosed long-term post-HT on transplant-related outcomes as well as future cardiovascular complications in this high-risk population. Furthermore, studies are needed to investigate the effects of glucose-lowering interventions (with lifestyle and/or medication) on progression of prediabetes to PTDM and prevention of (cardiovascular) complications.
The datasets presented in this article are not readily available due to privacy reasons. Reasonable requests to access the datasets should be directed to
This study involving human participants were reviewed and approved by Erasmus MC Ethics committee. The patients/participants provided their written informed consent to participate in this study.
SR participated in conception and design of the research, in the acquisition of the data, the statistical analysis, drafting the manuscript and critical revision of the final version of the manuscript. MG-S participated in conception and design of the research, in the acquisition of the data, drafting the manuscript and critical revision of the final version of the manuscript. JK participated in conception and design of the research, drafting the manuscript and critical revision of the final version of the manuscript. AC participated in the acquisition of the data, drafting the manuscript and critical revision of the final version of the manuscript. YT participated in drafting the manuscript and critical revision of the final version of the manuscript. FZ supervision, drafting the manuscript and critical revision of the final version of the manuscript AZ participated in conception and design of the research, supervision, drafting the manuscript and critical revision of the final version of the manuscript. OM participated in conception and design of the research, in the acquisition of the data, supervision, drafting the manuscript and critical revision of the final version of the manuscript.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The Supplementary Material for this article can be found online at:
ADA, American Diabetes Association; BMI, body mass index; CAV, cardiac allograft vasculopathy; CMV, cytomegalovirus; HbA1c, glycated hemoglobin; HT, heart transplantation; ISHLT, International Society for Heart and Lung Transplantation; LVAD, left ventricular assist device; OGTT, oral glucose tolerance test; OR, odds ratio; PTDM, post-transplantation diabetes mellitus.