Acute pancreatitis (AP) is a prevalent medical condition, affecting approximately 33.74 individuals per 100,000 population.1 Predominantly instigated by gallstone disease and alcohol abuse, AP constitutes a significant burden on global healthcare systems.2 Notably, hypertriglyceridemia (HTG) emerges as the third leading cause, contributing to about 10% of AP cases.2 Elevated triglyceride levels in the bloodstream, defined as fasting serum triglycerides of 150mg/dL (1.7mmol/L), serve as a pivotal trigger for pancreatitis, fostering the accumulation of free fatty acids and eliciting an inflammatory cascade within the pancreas.3 Severe HTG, characterized by triglyceride levels exceeding 500mg/dL, poses a substantial risk factor for pancreatitis development.4

Recent investigations have shed light on the nuanced presentation of lipogenic pancreatitis, showcasing its propensity for more severe clinical manifestations compared to non-lipogenic counterparts.5 Among individuals with hypertriglyceridemia-induced acute pancreatitis (HTG-AP), heightened triglyceride levels correlate with a more protracted hospitalization course, increased complication rates, prolonged stays, and elevated mortality rates.6,7

Crucially, managing hyperlipidemic acute pancreatitis hinges upon lipid-lowering interventions, with fibrates emerging as the foremost efficacious anti-hyperlipidemia agents in mitigating elevated triglyceride levels.6,8 Post-acute pancreatitis diabetes mellitus (PPDM-A) appears as a consequential metabolic sequelae, encompassing 80% of all exocrine pancreatic diabetes cases and accounting for 1.8% of adult diabetes instances.9,10 Exhibiting poor glycemic control, approximately 20.9% of PPDM-A patients necessitate insulin therapy within five years.10 Insights from existing literature suggest a discernible interplay between lipid metabolism and insulin resistance.11,12 Thus, this study elucidates the nexus between fibrates and diabetes after primary acute pancreatitis with hypertriglyceridemia, offering valuable insights into therapeutic modalities and long-term metabolic outcomes. Since it's very challenging to find the specific genetic marker SNP for PPDM-A in the Mendelian database, we decided to investigate the connection between lipid-lowering medications and PPDM-A from a different angle. We were curious to see if these drugs could reduce the risk of PPDM-A by lowering the chances of pancreatitis. Therefore, we used Mendelian randomization (MR) methods to determine whether there is a causal relationship between triglycerides and diabetes, and if so, two-step MR to determine whether pancreatitis partially mediates the effects.

Post-acute pancreatitis diabetes mellitus (PPDM-A) is a form of diabetes resulting from dysfunction of the exocrine pancreas. Although the precise etiology of this condition remains incompletely understood, it is associated with a heightened risk of pancreatic cancer and mortality compared to type 2 diabetes mellitus (T2DM). Our Mendelian randomization analysis unveiled a compelling causal connection between triglyceride levels and diabetes. Increased triglyceride levels in circulation can detrimentally affect insulin sensitivity, potentially attributed to genetic variations in the peroxisome proliferator-activated receptor-γ (PPAR-γ),15 or via the IkB kinase (IKK)/nuclear factor (NF)-κB pathway, linking the immune system to fat-induced insulin resistance.16 Impairment in insulin secretion or insulin resistance diminishes the activity of lipoprotein lipase (LPL), an enzyme crucial for triglyceride breakdown, resulting in elevated blood triglyceride levels, as LPL function is insulin-dependent.11 Glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1) plays a pivotal role in the regulation of LPL, facilitating its transportation from parenchymal cells to the luminal surface of capillary endothelial cells, essential for efficient lipolysis.11 Mutations in GPIHBP1 may predispose individuals to severe hypertriglyceridemia and pancreatitis,11 while the presence of GPIGBP1 autoantibodies has been associated with severe hypertriglyceridemia and recurrent acute pancreatitis.17

Hyperlipidemia is closely linked to diabetes. In our retrospective study, we discovered that lowering lipid levels can decrease the incidence of PPDM-A. In our two-step Mendelian randomization analysis, we identified a causal relationship between triglyceride levels and diabetes risk, with pancreatitis partially mediating this effect. Lowering triglyceride levels can reduce the likelihood of pancreatitis and, consequently, the overall risk of diabetes. This supports the findings of our retrospective study. Although our retrospective study was unable to obtain triglyceride measurements at the 3-month post-onset interval, extensive clinical evidence substantiates the triglyceride-lowering efficacy of fibrates.18,19 Notably, fenofibrate demonstrates 20–50% reductions in triglyceride levels during hypertriglyceridemia management, with pronounced efficacy observed particularly in patients manifesting metabolic syndrome or type 2 diabetes.20 These findings collectively highlight the promising therapeutic potential of fenofibrate for PPDM-A prophylaxis.

Fibrates, derived from fibric acid, reduce triglyceride (TG) levels and suppress hepatic apoC-III production.8 Furthermore, they augment LPL-mediated lipolysis through activation of transcription factors associated with Peroxisome proliferator-activated receptor-α (PPAR-α).8 Despite limited research on fibrates and PPDM-A, existing studies indicate potential benefits, such as improving insulin sensitivity by reducing plasma triglycerides and ameliorating liver and muscle steatosis.21,22 Additionally, fibrates exhibit therapeutic promise in diabetic retinopathy (DR) management, with documented effects on retinal vascular permeability reduction and preservation of white matter. Moreover, fibrates down-regulate vascular endothelial growth factor and mitigate endothelial and pericyte loss, offering therapeutic potential in managing DR-associated complications.23 Notably, fibrates have demonstrated efficacy in slowing the progression of diabetic eye diseases, including diabetic macular edema and proliferative diabetic retinopathy, with reduced reliance on laser treatment.23–26

Our study also identified several independent risk factors associated with PPDM-A, including gender, hyperglycemia at admission, recurrence of pancreatitis, the severity of pancreatitis, and fibrate use. These risk factors have been reported in multiple studies. As highlighted in a review, patients under 40 years of age, male, and with either a lean or overweight physique, who develop pancreatitis and subsequent exocrine pancreatic insufficiency, are at the highest risk for developing PPDM-A.27 Additionally, admission hyperglycemia has been identified as an independent risk factor in a retrospective study of 820 patients using machine learning algorithms.28 Patients with recurrent pancreatitis often experience more difficult glycemic control and are considered at increased risk for further recurrence. Recurrent episodes of pancreatitis can impair the endocrine function of the pancreas and also lead to changes in pancreatic volume. After two or more episodes of AP, the total volume of the pancreas significantly decreases. It is known that the highest proportion of pancreatic islets is located in the tail of the pancreas, rather than the head or body. Following two or more episodes of AP, there is a significant reduction in the pancreatic tail, which correlates with a reduction in β-cell mass.29 A recent prospective cohort study involving 187 youth patients (aged under 21 years) found that CRP levels and the severity of pancreatitis serve as independent risk factors for PPDM-A.30 However, in our study, CRP did not show a statistically significant association with the risk of PPDM-A. This may be attributed to the fact that CRP levels were measured at admission, typically within hours of pancreatitis onset, while CRP peaks usually occur 24–48h after the initial onset. This temporal discrepancy may account for the observed result. Future prospective, multicenter studies are warranted to further explore this association.

Early identification and prompt intervention for PPDM-A are crucially important. Begin the treatment plan with a focus on behavioral and lifestyle interventions, which should encompass alcohol withdrawal support, a well-balanced diet, regular exercise, and attention to neurological, cognitive, and mental health concerns, as well as effective pain control strategies.27 It is also crucial to incorporate medication management, including the use of dietary fiber, pancreatic enzyme supplementation, insulin therapy, oral hypoglycemic agents, and appropriate osteoporosis treatment.27 In our research, we discovered that the act of lowering lipid levels has shown to have a positive impact on the prevention of PPDM-A. This discovery presents a promising new avenue for both preventing and treating PPDM-A. However, to solidify and validate our findings, further randomized controlled studies will be required.

Several limitations of this study warrant acknowledgment. Firstly, its retrospective single-center design necessitates further investigation in larger, multicenter settings to validate the association between lipid-lowering therapy and PPDM-A. Secondly, the study predominantly focused on the association between fibrates and PPDM-A, necessitating additional research to explore the relationship between other lipid-lowering agents and PPDM-A. Furthermore, the impact of lipid-lowering medication duration on PPDM-A was inadequately explored due to the study's retrospective nature. Future studies should address these limitations to provide comprehensive insights into the association between lipid-lowering medications and PPDM-A.

In summary, our research highlights the potential benefits of using fibrate treatment to reduce the risk of PPDM-A in comparison to untreated patients. Furthermore, there is a direct correlation between triglyceride levels and the risk of diabetes, which is partly influenced by pancreatitis. These results underscore the significance of using fibrates to assess the prevention of PPDM-A.

Jiali Xu and Nana Deng contributed equally to this study. Jiali Xu, Mingming Deng, and Gang Luo contributed to the study design. Jiali Xu, Nana Deng, and Zhouyue Zhang contributed to data acquisition. Jiali Xu, Nana Deng, Zhouyue Zhang, Mingming Deng, and Gang Luo contributed to statistical analysis, data interpretation, writing the manuscript, literature search and funds collection.

This study protocol was approved by the Ethics Committee of the Affiliated Hospital of Southwest Medical University with batch number KY2023253.

This work was supported by the Science and Technology Department of Sichuan Province (grant number: 2022YFS0626) and the Luzhou Municipal People's Government-Southwest Medical University Science and Technology Strategic Cooperation Project (grant number: 2020LZXNYDZ02).

The authors have no conflict of interests to declare.