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Persistent chylomicronemia is a genetic recessive disorder that is classically caused by familial chylomicronemia syndrome (FCS), but it also has multifactorial causes. The disorder is associated with the risk of recurrent acute pancreatitis. Plozasiran is a small interfering RNA that reduces hepatic production of apolipoprotein C-III and circulating triglycerides. In a phase 3 trial, we randomly assigned 75 patients with persistent chylomicronemia (with or without a genetic diagnosis) to receive subcutaneous plozasiran (25 mg or 50 mg) or placebo every 3 months for 12 months. The primary end point was the median percent change from baseline in the fasting triglyceride level at 10 months. Key secondary end points were the percent change in the fasting triglyceride level from baseline to the mean of values at 10 months and 12 months, changes in the fasting apolipoprotein C-III level from baseline to 10 months and 12 months, and the incidence of acute pancreatitis. At baseline, the median triglyceride level was 2044 mg per deciliter. At 10 months, the median change from baseline in the fasting triglyceride level (the primary end point) was -80% in the 25-mg plozasiran group, -78% in the 50-mg plozasiran group, and -17% in the placebo group (P<0.001). The key secondary end points showed better results in the plozasiran groups than in the placebo group, including the incidence of acute pancreatitis (odds ratio, 0.17; 95% confidence interval, 0.03 to 0.94; P = 0.03). The risk of adverse events was similar across groups; the most common adverse events were abdominal pain, nasopharyngitis, headache, and nausea. Severe and serious adverse events were less common with plozasiran than with placebo. Hyperglycemia with plozasiran occurred in some patients with prediabetes or diabetes at baseline. Patients with persistent chylomicronemia who received plozasiran had significantly lower triglyceride levels and a lower incidence of pancreatitis than those who received placebo. (Funded by Arrowhead Pharmaceuticals; PALISADE ClinicalTrials.gov number, NCT05089084.).

The combination of rectally administered indomethacin and placement of a prophylactic pancreatic stent is recommended to prevent pancreatitis after endoscopic retrograde cholangiopancreatography (ERCP) in high-risk patients. Preliminary evidence suggests that the use of indomethacin might eliminate or substantially reduce the need for stent placement, a technically complex, costly, and potentially harmful intervention. In this randomised, non-inferiority trial conducted at 20 referral centres in the USA and Canada, patients (aged ≥18 years) at high risk for post-ERCP pancreatitis were randomly assigned (1:1) to receive rectal indomethacin alone or the combination of indomethacin plus a prophylactic pancreatic stent. Patients, treating clinicians, and outcomes assessors were masked to study group assignment. The primary outcome was post-ERCP pancreatitis. To declare non-inferiority, the upper bound of the two-sided 95% CI for the difference in post-ERCP pancreatitis (indomethacin alone minus indomethacin plus stent) would have to be less than 5% (non-inferiority margin) in both the intention-to-treat and per-protocol populations. This trial is registered with ClinicalTrials.gov (NCT02476279), and is complete. Between Sept 17, 2015, and Jan 25, 2023, a total of 1950 patients were randomly assigned. Post-ERCP pancreatitis occurred in 145 (14·9%) of 975 patients in the indomethacin alone group and in 110 (11·3%) of 975 in the indomethacin plus stent group (risk difference 3·6%; 95% CI 0·6–6·6; p=0·18 for non-inferiority). A post-hoc intention-to-treat analysis of the risk difference between groups showed that indomethacin alone was inferior to the combination of indomethacin plus prophylactic stent (p=0·011). The relative benefit of stent placement was generally consistent across study subgroups but appeared more prominent among patients at highest risk for pancreatitis. Safety outcomes (serious adverse events, intensive care unit admission, and hospital length of stay) did not differ between groups. For preventing post-ERCP pancreatitis in high-risk patients, a strategy of indomethacin alone was not as effective as a strategy of indomethacin plus prophylactic pancreatic stent placement. These results support prophylactic pancreatic stent placement in addition to rectal indomethacin administration in high-risk patients, in accordance with clinical practice guidelines. US National Institutes of Health.

Saxagliptin, a new oral antihyperglycemic drug in the DPP-4 inhibitor class, had no effect on the risk of cardiovascular events in patients with type 2 diabetes. Although the drug does not increase cardiovascular risk, it also does not provide cardiovascular benefit. Type 2 diabetes mellitus doubles the risk of major cardiovascular complications in patients with and in patients without established cardiovascular disease, 1 – 3 such that the majority of patients with diabetes die of cardiovascular diseases. 4 Although improved glycemic control has repeatedly been shown to reduce microvascular diabetic complications, 5 uncertainty remains regarding whether any particular glucose-lowering strategy, or specific therapeutic agent, is safe from a cardiovascular standpoint or can actually lower cardiovascular risk. With the possible exception of trials of metformin 6 and insulin, 7 most reported trials to date evaluating the effects on cardiovascular outcomes of specific glucose-lowering strategies or medications either have . . .

Acute pancreatitis (AP) is associated with a high incidence of acute kidney injury (AKI). This study aimed to develop a nomogram for predicting the early onset of AKI in AP patients admitted to the intensive care unit. Clinical data for 799 patients diagnosed with AP were extracted from the Medical Information Mart for Intensive Care IV database. Eligible AP patients were randomly divided into training and validation cohorts. The independent prognostic factors for the early development of AKI in AP patients were determined using the all-subsets regression method and multivariate logistic regression. A nomogram was constructed for predicting the early occurrence of AKI in AP patients. The performance of the nomogram was evaluated based on the area under the receiver operating characteristic curve (AUC), calibration curves and decision curve analysis (DCA). Seven independent prognostic factors were identified as predictive factors for early onset AKI in AP patients. The AUC of the nomogram in the training and validation cohorts were 0.795 (95% CI, 0.758-0.832) and 0.772 (95% CI, 0.711-0.832), respectively. The AUC of the nomogram was higher compared with that of the BISAP, Ranson, APACHE II scores. Further, the calibration curve revealed that the predicted outcome was in agreement with the actual observations. Finally, the DCA curves showed that the nomogram had a good clinical applicability value. The constructed nomogram showed a good predictive ability for the early occurrence of AKI in AP patients.

Emerging data in the past few years suggest that acute, recurrent acute (RAP), and chronic pancreatitis (CP) represent a disease continuum. This review discusses the similarities and differences in the epidemiology of RAP and CP. RAP is a high-risk group, comprised of individuals at varying risk of progression. The premise is that RAP is an intermediary stage in the pathogenesis of CP, and a subset of RAP patients during their natural course transition to CP. Although many clinical factors have been identified, accurately predicting the probability of disease course in individual patients remains difficult. Future studies should focus on providing more precise estimates of the risk of disease transition in a cohort of patients, quantification of clinical events during the natural course of disease, and discovery of biomarkers of the different stages of the disease continuum. Availability of clinically relevant endpoints and linked biomarkers will allow more accurate prediction of the natural course of disease over intermediate- or long-term-based characteristics of an individual patient. These endpoints will also provide objective measures for use in clinical trials of interventions that aim to alter the natural course of disease.

Pancreatitis is the most common and serious complication of diagnostic and therapeutic ERCP. The aim of this study is to examine the potential patient- and procedure-related risk factors for post-ERCP pancreatitis in a prospective multicenter study. A 160-variable database was prospectively collected by a defined protocol on patients undergoing diagnostic or therapeutic ERCP at 15 centers in the Midwest Pancreaticobiliary Group and participating in a randomized controlled study evaluating whether prophylactic corticosteroids will reduce the incidence of post-ERCP pancreatitis. Data were collected prior to the procedure, at the time of procedure, and 24-72 h after discharge. Post-ERCP pancreatitis was diagnosed and its severity graded according to consensus criteria. Of the 1,115 patients enrolled, diagnostic ERCP with or without sphincter of Oddi manometry (SOM) was performed in 536 (48.1%) and therapeutic ERCP in 579 (51.9%). Suspected sphincter of Oddi dysfunction (SOD) was the indication for the ERCP in 378 patients (33.9%). Pancreatitis developed in 168 patients (15.1%) and was graded mild in 112 (10%), moderate in 45 (4%), and severe in 11(1%). There was no difference in the incidence of pancreatitis or the frequency of investigated potential pancreatitis risk factors between the corticosteroid and placebo groups. By univariate analysis, the incidence of post-ERCP pancreatitis was significantly higher in 19 of 30 investigated variables. In the multivariate risk model, significant risk factors with adjusted odds ratios (OR) were: minor papilla sphincterotomy (OR: 3.8), suspected SOD (OR: 2.6), history of post-ERCP pancreatitis (OR: 2.0), age <60 yr (OR: 1.6), > or =2 contrast injections into the pancreatic duct (OR: 1.5), and trainee involvement (OR: 1.5). Female gender, history of recurrent idiopathic pancreatitis, pancreas divisum, SOM, difficult cannulation, and major papilla sphincterotomy (either biliary or pancreatic) were not multivariate risk factors for post-ERCP pancreatitis. This study emphasizes the role of patient factors (age, SOD, prior history of post-ERCP pancreatitis) and technical factors (number of PD injections, minor papilla sphincterotomy, and operator experience) as the determining high-risk predictors for post-ERCP pancreatitis.

BackgroundRecent meta-analyses suggested diclofenac may be superior to indomethacin in preventing post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The aim of our study was to compare the efficacy of 100 mg rectal indomethacin versus diclofenac on PEP incidences.DesignThis multicentre, double-blinded, randomised controlled trial was conducted in nine tertiary centres in China. Patients with low and high risk for PEP and native papilla were randomly allocated (1:1) to receive 100 mg diclofenac or 100 mg indomethacin rectally before ERCP. The primary outcome was the occurrence of PEP defined by the Cotton consensus. The intention-to-treat principle was conducted for the analysis.ResultsThe trial was terminated early for futility after the predetermined first interim analysis. Between June 2023 and May 2024, 1204 patients were randomised into the diclofenac group (n=600) or indomethacin group (n=604). Baseline characteristics were balanced. The primary outcome occurred in 53 patients (8.8%) of 600 patients allocated to the diclofenac group and 37 patients (6.1%) of 604 patients allocated to the indomethacin group (relative risk 1.44; 95% CI 0.96 to 2.16, p=0.074). PEP occurred in 35 (14.2%) of 247 high-risk patients in the diclofenac group and 26 (9.8%) of 266 high-risk patients in the indomethacin group (p=0.124). PEP incidences were also comparable in low-risk patients between the two groups (18/353 (5.1%) vs 11/338 (3.3%), p=0.227). Other ERCP-related complications did not differ between the two groups.ConclusionPre-procedure 100 mg rectal diclofenac was not superior to the same dose of rectal indomethacin regarding preventing PEP. These findings supported current clinical practice guidelines of 100 mg indomethacin or diclofenac for PEP prophylaxis in patients without contraindications.Trial registration numberClinicalTrials.gov (NCT05947461).

Hypertriglyceridemia (HTG) represents a major health problem with prevalence exceeding 30% in the U.S. The present study aims to assess the effect of elevated serum triglyceride (TG) levels on the severity of acute pancreatitis (AP). Prospectively enrolled AP patients were categorized into normal, mild, moderate, and severe/very severe categories based on their TG levels and compared in respect to demographics, comorbidities, and clinical outcomes. Multivariate analysis determined whether elevated TG levels were independently associated with persistent organ failure. Two hundred and one out of 400 AP patients had serum TGs measured within 72 h of presentation, of which 115 had normal TG levels and 86 HTG (20 mild, 41 moderate, and 25 severe/very severe). Patients with HTG were of younger age (44 vs. 52 years), predominantly male (65% vs. 45%), obese (57% vs. 34%), diabetic (38% vs. 17%), and developed more frequently persistent organ failure (40% vs. 17%) compared with those with normal TGs (P<0.02). The rate of persistent organ failure increased proportionally with HTG severity grades (17% when normal TGs, 30% in mild, 39% in moderate, and 48% in severe/very severe HTG, Ptrend<0.001). On multivariate analysis controlling for age, gender, body mass index, diabetes, and alcohol etiology, moderate HTG (odds ratio (OR), 2.6; P=0.04) and severe/very severe HTG (OR, 4.9; P=0.009) were independently associated with persistent organ failure. Elevated serum TGs in AP patients are independently and proportionally correlated with persistent organ failure regardless of etiology. TG-mediated lipotoxicity may be an attractive target to design novel interventions for severe AP.

Successful biliary cannulation is a prerequisite and important component of endoscopic retrograde cholangiopancreatography, but conventional cannulation methods (CCMs) have a postendoscopic retrograde cholangiopancreatography pancreatitis (PEP) rate of 14.1% in patients at high risk for PEP. The aim of this study was to evaluate the effectiveness and safety of needle-knife fistulotomy (NKF), compared with a CCM, when used for primary biliary access in patients at high risk for developing PEP. A total of 207 patients with one or more risk factors for PEP were prospectively enrolled. The patients were randomly allocated to one of 2 groups according to the primary biliary cannulation technique (NKF or CCM). We compared biliary cannulation success rates, cannulation and procedure times, and the incidence of adverse events, including PEP, between the groups. The mean number of PEP risk factors was similar between the groups (NKF, 2.2 ± 1.0; CCM, 2.2 ± 0.9). PEP occurred in 8 patients in the CCM group and in no patients in the NKF group (9.2% vs 0%, P < 0.001). The rates of other adverse events did not differ between the groups. The biliary cannulation success rate was high in the NKF group, but relatively low in the CCM group, possibly because of the stringent failure criteria aimed at reducing PEP. However, the mean cannulation and total procedural times were longer in the NKF group than in the CCM group. NKF is an effective and safe procedure to gain primary biliary access in patients at high risk for developing PEP. ClinicalTrials.gov, NCT02916199.

Biliary cannulation is frequently the most difficult component of endoscopic retrograde cholangiopancreatography (ERCP). Techniques employed to improve safety and efficacy include wire-guided access and the use of sphincterotomes. However, a variety of options for these techniques are available and optimum strategies are not defined. We assessed whether the use of endoscopist- vs. assistant-controlled wire guidance and small vs. standard-diameter sphincterotomes improves safety and/or efficacy of bile duct cannulation. Patients were randomized using a 2 × 2 factorial design to initial cannulation attempt with endoscopist- vs. assistant-controlled wire systems (1:1 ratio) and small (3.9Fr tip) vs. standard (4.4Fr tip) sphincterotomes (1:1 ratio). The primary efficacy outcome was successful deep bile duct cannulation within 8 attempts. Sample size of 498 was planned to demonstrate a significant increase in cannulation of 10%. Interim analysis was planned after 200 patients-with a stopping rule pre-defined for a significant difference in the composite safety end point (pancreatitis, cholangitis, bleeding, and perforation). The study was stopped after the interim analysis, with 216 patients randomized, due to a significant difference in the safety end point with endoscopist- vs. assistant-controlled wire guidance (3/109 (2.8%) vs. 12/107 (11.2%), P=0.016), primarily due to a lower rate of post-ERCP pancreatitis (3/109 (2.8%) vs. 10/107 (9.3%), P=0.049). The difference in successful biliary cannulation for endoscopist- vs. assistant-controlled wire guidance was -0.5% (95% CI-12.0 to 11.1%) and for small vs. standard sphincerotome -0.9% (95% CI-12.5 to 10.6%). Use of the endoscopist- rather than assistant-controlled wire guidance for bile duct cannulation reduces complications of ERCP such as pancreatitis.