Risk of cardiovascular disease and mortality in patients with diabetes and a history of acute pancreatitis: a nationwide cohort study

In this large-scale, national cohort study, the independent risk of stroke, MI, and mortality was significantly higher in diabetic participants with a history of AP compared to those without a history of AP at 10-year follow-up . Adjusted HRs were 1.5 to 2.4 after controlling for important confounding variables. The results of this study suggest that active management of cardiovascular risk factors is necessary in diabetic patients with a history of AP.

A recent similar large-scale cohort study reported that the adjusted RR for acute cardiovascular disease was 1.76 (95% CI, 1.47-2.12) in patients with AP, which is comparable to our result.5. However, unlike our study, the report did not adjust for important confounders such as smoking and alcohol. Additionally, the report did not consider the temporal sequence of AP and CVD onset over the research period, making it difficult to assess causality. In contrast, our study shows possible causation because we constructed a separate cohort of diabetic patients with a history of AP but no CVD, and also performed follow-up to assess CVD incidence or death over a long period. Another similar cohort study suggested that the risk of acute coronary syndrome is higher in patients with a first PA than in those without PA (adjusted HR 2.46, in diabetic patients)6. The study also showed that about a third of acute coronary syndromes developed within a month of the onset of AP. However, the study did not include a latency period, which implies the possibility of including many CVD patients before AP. Additionally, the study also did not adjust for important factors such as smoking or BMI.

AP is an acute systemic inflammatory process that is associated with variable involvement of one or more organ systems to varying degrees11. In particular, the cardiovascular system can be affected at all stages of AP, including hemodynamic, cardiac rhythm and pericardial changes. Therefore, fluid resuscitation is important in the early stages of AP12,13,14. AP is also known to be associated with microcirculation disturbances15. These changes are hypothesized to play an important role in short-term cardiovascular outcomes and may affect the occurrence of CVD through long-term atherosclerosis.5. The release of several inflammatory cytokines such as tumor necrosis factor α, interleukin (IL)-6, IL-10, and monocyte chemoattractant protein chemokines-1 in the process of PA16 may be associated with the pathogenesis of atherosclerosis17.18. However, further research is needed to elucidate the exact mechanism.

As shown in Table 1, insulin or additional antidiabetic agents are often required for diabetic patients with a history of AP. This suggests that BP may be associated with the level of endocrine dysfunction, which appears to affect the severity of diabetes, which in turn may increase CVD risk. A previous meta-analysis showed that prediabetes and/or diabetes were observed in 37% of individuals after AP, with a relative risk of 2.7 at 5 years after diagnosis.19. As a result, a large portion of diabetic participants with a history of AP could belong to pancreatogenic or type 3c diabetes.20. However, it is difficult to confirm the causal relationship between AP and diabetes in our study, as we identified diabetic participants who had a history of AP at baseline.

Cox proportional hazards regression analysis showed that the highest HR was all-cause mortality (2.353), followed by MI (1.998) and stroke (1.534) from Model 5 (Table 2 ). The simple sum of the incidence rate per 1000 person-years for cardiovascular disease was 16.76 and that of all-cause mortality was 34.88 among participants with a history of AP. Therefore, it is expected that other contributing factors to mortality other than CVD clearly exist. Although we were unable to investigate the cause of death for each patient, some patients may have died of various malignant neoplasms known to increase with diabetes, particularly the increased risk of pancreatic cancer after a diagnosis of AP.21. Additionally, some patients may have died from other life-threatening complications of diabetes such as infection or end-stage renal failure.22. Interestingly, subgroup analysis showed that mortality was higher in younger participants (23. It is known that the mortality rate is higher when AP progresses to CP24, and thus several factors associated with the AP-CP sequence may have greatly contributed to the increased mortality in young participants in our study. However, as the occurrence of CP was not assessed as an outcome in our study, it was difficult to determine the substantial impact of CP.

In fact, the risk of CVD was higher in patients with CP (adjusted RR, 3.42) than in those with AP (adjusted RR, 1.76) in the aforementioned study.5. An increased risk of CVD in patients with CP has also been reported in other studies, with a range of 1.27 to 1.45325,26,27. However, caution should be exercised in interpreting the results due to the heterogeneity of CP patients. With respect to research based on claims data such as our study, it is highly likely that true CP patients cannot be correctly identified using diagnostic codes alone. In our view, a more careful operational definition is needed to perform the so-called big data study for CP. Accordingly, we recognized that it was difficult to define CP as a study outcome.

There are several limitations to our study. First, results may vary depending on the etiology and severity of AP, which was not taken into account in our study. This is a somewhat intrinsic limitation of the NHIS database. Second, as mentioned above, participants who develop diabetes after AP are likely to be diagnosed with type 3c diabetes rather than T2DM. However, it was difficult to identify the number of these participants included in this study. Third, the medications administered to our participants were not taken into account. In diabetic patients, drugs such as antithrombotic agents28.29 or metformin5.30 may affect cardiovascular outcomes and mortality. Fourth, we did not assess other conditions such as angina, heart failure, or peripheral arterial disease that fall under the category of cardiovascular disease.31. Finally, there were statistically significant differences regarding several characteristics of the two groups, such as baseline characteristics including age, BMI, alcohol consumption, and smoking history, which may directly affect cardiovascular disease. . In addition, information on smoking and alcohol consumption obtained from surveys is likely to be underestimated. These factors were difficult to manipulate by matching because there were many risk factors shared by AP and CVD. AP appears to play some role as we were able to obtain significant results even after adjusting for confounders by the Cox proportional hazard ratio method. Nonetheless, the strength of our study is that we presented CVD risk and mortality, adjusting for important confounding variables by long-term follow-up, for history of AP in a relatively uniform and large number of participants. diabetics who have undergone health examinations.