Reduced Cardiovascular Risk Indicated by Changes in Triglyceride-Glucose Index After Pancreas Transplantation

Introduction

Pancreatic transplant is the best causal treatment for type I diabetes. It may also be a therapeutic option in patients with refractory type II diabetes mellitus. Diabetes mellitus is a systemic disease that, in the long term, may lead to severe disability and even death [1]. Despite the established indications, pancreas transplantations are performed much less frequently than are renal or liver transplantations [2]. This is surprising, since the number of individuals with diabetes in Poland exceeds 2.5 million, about 10% of whom have type I diabetes [3]. It is estimated that approximately 10% of patients with diabetes may benefit from pancreas or simultaneous pancreas-kidney transplantation.

Pancreas transplantation is a complex and difficult surgical procedure, with surgical as well as medical complications not being uncommon in the early postoperative period. The complications are the consequences of a complicated surgery, long hospital stay, and immunosuppressive therapy. The awareness of the risks and the low level of knowledge about the long-term benefits of pancreas transplantations among physicians and patients limit the number of procedures performed.

Pancreas transplantations were repeatedly proven to provide long-term independence from exogenous insulin or, less frequently, to stabilize glycemic levels, with a significant reduction in insulin requirements [4]. Correlating the results of pancreatic transplant with a recognized prognostic parameter should effectively verify the validity of this method of diabetes treatment.

The triglyceride-glucose (TyG) index is a well-established tool for determining insulin resistance and the risk of non-alcoholic fatty liver disease or arterial stenosis in patients with diabetes [5–7]. The TyG index value has been shown to be a reliable predictor of the long-term risk of cardiovascular episodes.

The purpose of this study is to evaluate the potential reduction in cardiovascular risk, using the TyG index as a surrogate marker, in patients undergoing pancreas transplantation.

Material and Methods

The analysis was conducted on data obtained from 86 patients undergoing pancreas transplantation at the Department of General and Transplantation Surgery, Medical University of Warsaw. The surgeries were performed from January 2016 to May 2025. All patients had been qualified for surgery according to the same standards. Patients underwent transplantation surgery according to a standardized surgical procedure as developed by a team from the Department of General and Transplantation Surgery at the Medical University of Warsaw. A 4-drug immunosuppression regimen including tacrolimus, mycophenolate mofetil, glucocorticosteroids, and induction of immunosuppressive treatment with rabbit anti-human thymocyte immunoglobulin (thymoglobulin) was used.

Of the 86 patients, 22 underwent pancreas transplant alone. One patient underwent a pancreas transplant after a prior kidney transplant. A total of 49 recipients received a simultaneous pancreas-kidney transplant. One patient received a simultaneous pancreas-liver transplant.

Serum triglyceride and glucose levels as recorded in milligrams per deciliter (mg/dL) at the stage of qualification for transplantation and at 1, 3, 6, and 12 months after transplantation were retrospectively analyzed within the described group of transplant recipients. For each of the points on the timeline, the TyG index was calculated according to the appropriate formula, as the natural logarithm of the product of the triglyceride level and one-half of the serum glucose concentration.

From 81 patients, complete data were obtained for 14 patients (17.3%). No data from before and from at least 1 post-transplantation measurement point could be found in only 5 patients, facilitating a trend analysis in 76 pancreas recipients (93.8%). The deficiencies in the database were due to the individualized approach to each patient. Follow-up visits at our center were managed according to the patients’ needs rather than according to a uniform, rigid pattern.

Two mathematical models were used. A repeated measures ANOVA model was used for the group of 14 patients with complete data. For the 76 patients with pretransplantation results and at least 1 posttransplantation result, a repeated measures analysis was performed with the measurement points at 1 month and/or 3 months and those at 6 months and/or 12 months being analyzed collectively. Next, the trends for the changes in glucose and triglyceride levels, as well as in the TyG index, were analyzed along the timeline for the entire study group.

Results

TREND ANALYSIS OF TYG INDEX VALUES AT CONSECUTIVE TIME POINTS: BEFORE TRANSPLANTATION AND AT 1, 3, 6, AND 12 MONTHS AFTER TRANSPLANTATION:

In the first step, the repeated measures ANOVA model was applied to the group of patients for whom complete data were available (n=14), showing a statistically significant effect of time (P<0.001). However, in pairwise comparisons, only the difference between the time points before and 12 months after transplantation was statistically significant, which limits the interpretation of the conclusions of this analysis. Due to the incompleteness of data in a wider group of patients, the main analysis was performed using a linear mixed model to account for missing observations.

The mixed model showed a significant effect of time on the TyG index value [F(4, ~65)=21.0, P<0.001]. The mean TyG index value decreased significantly as early as 1 month after transplantation and remained at a reduced level in subsequent months (P<0.001 for all comparisons relative to baseline). The greatest decrease was observed between the pre-transplant period and 1 month after the procedure; the differences between individual post-transplant periods were not significant, suggesting a rapid therapeutic effect and stabilization.

ANALYSIS OF TRENDS AT MONTHS 1 AND 3 COLLECTIVELY, AND AT MONTHS 6 AND 12 COLLECTIVELY:

The trend analysis was performed for the TyG index values at 3 time points: before transplantation, early follow-up, and late follow-up. The mean TyG index decreased significantly as early as at 1 to 3 months (M=6.85 vs 8.97; P<0.001; d=0.91; Figure 1), the decrease also persisted after 6 to 12 months (M=6.60 vs 9.16; P<0.001; d=1.25; Figure 2). The difference between the early and late follow-up time points was smaller but remained significant (P=0.024; d=0.41; Figure 3). Due to the non-normality of distribution (Shapiro-Wilk P<0.001), a Wilcoxon test was also performed, which confirmed the significance of all comparisons (P<0.01).

GLUCOSE LEVELS:

A significant decrease in glucose levels was observed over time (F(4, 52)=29.2; P<0.001), mainly between baseline and month 1. At subsequent time points, the values remained stable, indicating a sustained improvement in glycemic control after transplantation (Figure 4).

TRIGLYCERIDES:

Triglyceride concentration changed significantly over time (F[4, 28]=5.98; P=0.001). After an increase at months 1 to 3, a gradual decline was observed with the lowest level at 12 months (Figure 5).

AVERAGE TYG INDEX OVER TIME:

A repeated measures ANOVA model was used to assess changes in TyG index values over time, encompassing the 5 time points (0, 1, 3, 6, and 12 months after transplantation). A significant effect of time was observed (F[4, 52]=6.27; P<0.001). The value of the TyG index declined steadily, with the highest and the lowest levels being observed before transplantation and after 12 months, respectively. The observed trend suggests a gradual and sustained improvement in metabolic parameters (Figure 6).

Discussion

Pancreas transplantation has been a modality of diabetes treatment for more than 50 years. Over this time, the treatment method has undergone numerous modifications, finally being refined to achieve satisfactory treatment results of 12-month transplant survival rates of approximately 90% [8]. In our center, the function of the transplanted pancreas was maintained after 1 year in 96.43% of recipients, with nearly 98% of organ recipients surviving at least 1 year after the procedure. These results support the relevance of our findings, which are comparable with outcomes reported by leading pancreas transplant centers worldwide.

Our study demonstrates that pancreas transplantation is associated with a long-term reduction in the risk of cardiovascular complications – the most common cause of death worldwide – as measured using the TyG index as a surrogate marker, at several months of follow-up [9]. The procedure also significantly improved glycemic control and body fat metabolism, with high statistical significance observed despite the relatively small patient population. These findings were confirmed using 2 different statistical models.

A limitation of the presented study is the lack of a control group, which would allow for a more objective comparison of the results. The authors considered it unethical to seek patients with diabetes who met the indications for pancreas transplantation and then deliberately observe them without attempting to implement the best available treatment. We noted that the biochemical parameters recorded at the beginning of each patient’s follow-up already reflected many years of advanced diabetes along with associated comorbidities. For this reason, it is reasonable to compare these baseline results with those observed after pancreas transplantation.

As has been repeatedly reported, early surgical complications remain a major challenge in pancreas transplantation. Worldwide, the most common complication is early organ thrombosis, which occurs in 3.7% of recipients of simultaneous pancreas-kidney transplant and 5.9% of pancreas transplant alone recipients [10]. One case of transplant thrombosis in a pancreas transplant alone recipient occurred in our center, for an overall rate of 1.2% of pancreatic thrombosis cases in the entire study group. With regard to simultaneous pancreas-kidney transplant recipients, the rate was 0% in the total of 49 cases. The second most frequently reported complication, requiring prompt surgical or medical interventions, is pancreatitis [11]. We repeatedly observed postoperative inflammation of the transplanted pancreas, diagnosed on the basis of imaging studies and elevation of serum amylase and lipase levels. Careful monitoring and prompt intervention in response to abnormal findings allowed most cases to be managed without the need for reoperation. One case of organ loss was recorded in the study group due to increased inflammatory changes in the early postoperative period. The third case of organ loss within the study group was due to a leaking duodeno-intestinal anastomosis (1.2% for the study group). In the literature, this complication accounts for approximately 2.5% to 2.9% of pancreas transplants [12,13].

Pancreas transplant alone and pancreas-kidney transplants are pursued exclusively in patients with severe diabetes and coexisting severe or rapidly progressive complications, such as KDIGO grade V renal failure [14]. This group of patients, as has been repeatedly demonstrated, benefits tremendously from pancreas transplantation, despite the risk of complications amounting to several percent. Moreover, simultaneous pancreas-kidney transplantation has been shown to provide greater benefits for patients with diabetes and end-stage renal disease than kidney transplantation from a living donor, followed by treatment of diabetes with exogenous insulin [15].

The TyG index was originally developed as a surrogate parameter for the determination of tissue insulin resistance [16]. Over several years, it has been validated and adapted as a reliable parameter to determine the risk of cardiovascular complications [17,18]. The TyG index has already been used multiple times in transplant recipients. The benefits of kidney transplantation for cardiovascular risk have been demonstrated with the TyG index [19]. The utility of the TyG index as a predictor of cardiovascular risk and a predictor of overall mortality was demonstrated in a group of nearly 1000 patients undergoing liver transplantation [19]. In addition, it was demonstrated that the TyG index can be successfully used as a marker of increased risk of diabetes after transplantation in heart transplant recipients. The TyG index has also been studied as a risk factor for developing a severe form of pancreatitis in patients treated for native pancreatitis [20].

To date, the effect of pancreas transplantation on the decrease in the risk of cardiovascular episodes has not been described in terms of the TyG index. The authors are aware of the limitations of the small size of the study group. All patients who underwent pancreas transplantation were included in the analysis. An additional limitation was the fact that only a proportion of patients attended follow-up visits at the scheduled time points and completed the recommended examinations. In many cases, good graft function of the transplanted pancreas resulted in progressively poorer adherence to follow-up visits.

A key strength of this analysis is the demonstration of statistically significant results. Pancreas transplantation was associated with improvements in metabolic parameters, suggesting a reduction in long-term cardiovascular risk in patients with type 1 diabetes. However, this observation should be confirmed in a larger group of patients.

Conclusions

On the basis of a detailed analysis in a group of transplant recipients (pancreas transplant alone, simultaneous pancreas-kidney, or, in 1 case, simultaneous pancreas-liver transplant) who underwent treatment at a single center and according to a uniform scheme, a strong association between transplantation and the reduction of the TyG index was shown. In addition, as demonstrated using 2 statistical models, the TyG index values gradually decreased over the first 12 months after transplantation, suggesting a sustained improvement in metabolic risk factors associated with cardiovascular disease in this group of patients. Pancreas transplantation was associated with significant improvements in metabolic risk factors related to cardiovascular disease. Given the limitations of the present analysis, a prospective, randomized study is warranted.