The relationship between pre-existing diabetes mellitus and the severity of acute pancreatitis: Report from a large international registry

Abstract

Background/Objectives

The relationship between pre-existing diabetes mellitus (DM) and acute pancreatitis (AP) severity has not been established. We assessed the impact of pre-existing DM on AP severity in an international, prospectively ascertained registry.

Methods

APPRENTICE registry prospectively enrolled 1543 AP patients from 22 centers across 4 continents (8 US, 6 Europe, 5 Latin America, 3 India) between 2015 and 2018, and collected detailed clinical information. Pre-existing DM was defined a diagnosis of DM prior to AP admission. The primary outcome was AP severity defined by the Revised Atlanta Classification (RAC). Secondary outcomes were development of systemic inflammatory response syndrome (SIRS) or intensive care unit (ICU) admission.

Results

Pre-existing DM was present in 270 (17.5%) AP patients, of whom 252 (93.3%) had type 2 DM. Patients with pre-existing DM were significantly (p < 0.05) older (55.8 ± 16 vs. 48.3 ± 18.7 years), more likely to be overweight (BMI 29.5 ± 7 vs. 27.2 ± 6.2), have hypertriglyceridemia as the etiology (15% vs. 2%) and prior AP (33 vs. 24%). Mild, moderate, and severe AP were noted in 66%, 23%, and 11% of patients, respectively. On multivariable analysis, pre-existing DM did not significantly impact AP severity assessed by the RAC (moderate-severe vs. mild AP, OR = 0.86, 95% CI 0.63–1.18; severe vs. mild-moderate AP, OR = 1.05, 95% CI, 0.67–1.63), development of SIRS, or the need for ICU admission. No interaction was noted between DM status and continent.

Conclusion

About one in 5 patients with AP have pre-existing DM. Once confounding risk factors are considered, pre-existing DM per se is not a risk factor for severe AP.

Introduction

Acute pancreatitis (AP) is among the most common causes of gastrointestinal-related hospitalizations and its incidence has been increasing [1,2]. Although the overall mortality associated with AP is typically low, AP is associated with high morbidity, long-term sequelae, and substantial medical health care costs [[1], [2], [3]], especially among patients with greater severity of disease. Therefore, understanding the factors that contribute to AP severity is important.

Type 2 diabetes mellitus (DM) is a common medical condition affecting a significant proportion of adults in the US and it is associated with a 2–3 folds increase in the risk of AP [4,5]. Multiple factors appear to contribute to this increased risk. The risk is greater in patients with poorly controlled hyperglycemia and may be reduced by tighter glycemic control [6]. Other risk factors for AP are also more frequent in this population, such as obesity, gallstones, and hypertriglyceridemia [[7], [8], [9]]. Individuals with DM frequently have comorbidities that require treatment with medications, some of which can potentially cause AP [10].

Although pre-existing DM, i.e., diabetes mellitus present before AP, is a susceptibility risk factor, meaning has been associated with an increased risk for developing AP in observational studies [4,5], it is less clear if it also increases the severity of AP. In general, age and co-morbidities are risk factors for AP severity [11]. Individuals with pre-existing DM tend to be older and have a higher prevalence of comorbidities [9], and these confounders make it difficult to conclusively establish an independent association between pre-existing DM and AP severity. On the other hand, there is biological plausibility in the hypothesis that pre-existing DM might cause worse AP outcomes. Experimentally induced diabetes in mice causes aggravation of AP, with enhanced pancreatic inflammatory response, edema formation, and pulmonary injury [12,13].

A recent meta-analysis of 9 published studies concluded that pre-existing DM is associated with greater severity of AP [14]. The prevalence of pre-existing DM ranged from 12.6 to 26.8% and was associated with a greater risk of renal failure, need for and duration of intensive care unit (ICU) admission. However, there were several limitations of the studies included in the meta-analysis which affect the ability to accurately assess the relationship between pre-existing DM and AP severity. For example, of the 9 studies, only a subset assessed organ failure (n = 4), local complications (n = 3), or ICU admission (n = 3), and only one used the Revised Atlanta Classification [15] to evaluate disease severity. Therefore, the relationship between pre-existing DM and the severity of AP remains an unsettled question; in fact, this meta-analysis [14] emphasized the need for prospective studies to answer this question.

To establish whether pre-existing DM is indeed associated with AP severity, we investigated this potential relationship in a prospectively-ascertained cohort of patients with AP enrolled in the APPRENTICE study, which included 22 centers across 4 continents. Taking advantage of the large sample size of this cohort, the contribution of age, comorbidities, and other potential confounders could be examined.