Pancrelipase Improves Symptoms of Exocrine Pancreatic Insufficiency and Health-Related Quality of Life in a Real-World Population of Patients with Chronic Pancreatitis.

Pancreatic Enzyme Replacement Therapy in Post-Whipple Patients: Optimizing the Dose and Maximizing Compliance

Introduction: PERT is the standard of care treatment for EPI. Real-world data on patient experience with PERT is lacking. The aim of this patient survey was to assess patient understanding and their use of PERT. Methods: An IRB-approved survey of 75 members of Inspire’s Pancreatic Cancer and Pancreatitis Support communities (inspire.com) was conducted. Eligibility included having EPI secondary to chronic pancreatitis (CP), pancreatic cancer (PC), pancreatic surgery (PS), or acute pancreatitis (AP), and current or past PERT experience. 76% were male, 85% white, 56% age 50-69 yrs, 56% living in a large city/ suburb. 67% reported CP, 19% PC, 5% PS (non-CP/PC), 9% AP (no concomitant CP). PERT was prescribed by gastroenterologist/pancreatologist in 64%; oncologist 17%; surgeon 11%; others 8%. Results: 28% of respondents felt their physician did not provide detailed information about EPI and 31% did not get an explanation about how PERT works. 83% searched for EPI information mainly online. HCP counseling on need for chronic PERT use was reported in 67% of those on PERT (n=60) and 27% in those no longer on PERT (n=15). In the latter group, no patient took PERT for more than 5 years despite CP/PC history. 11% reported receiving no instructions on how and when to take PERT; 21% were instructed to take PERT with food or meals and no instructions for snacks, and 21% reported not taking PERT with any snacks. 59% were instructed to take PERT solely before or after eating and 56% were taking it as such. 36% reported PERT doses< 40,000 LU/meal. 10-15% did not understand how many capsules to take per meals or snacks. 24% decreased dosage mainly because they felt there will be no health consequences. 21% reported purposely skipping PERT mostly because they felt that PERT was not needed with every meal/snack. Patients stopped PERT mainly due to pill burden. 39% reported absence of follow-up by their physician on how they are doing since start of PERT. 84% of those with physician follow-up were asked about their EPI symptoms. Conclusion: Up to 1/3 of participants reported gaps in patient-physician dialogue regarding how to use PERT. More than half took PERT solely before or after eating. 36% of patients were underdosed (based on ACG Guidelines for CP). ∼ 1/4 skipped PERT or decreased the dose. Targeted education interventions are warranted to improve barriers to care and sequelae of untreated/undertreated EPI.

Treatment of pancreatic exocrine insufficiency (PEI) sounds easy because pancreatic enzyme replacement therapy (PERT) is safe and has virtually no side effects. There are recent guidelines turning the scientific evidence in concrete therapeutic recommendations [1, 2]. The paper by Kumar et al. in this issue of the Journal of Internal Medicine takes a bird eye's view screening a database of 74 million individuals, matching 20,700 chronic pancreatitis and pancreatic cancer patients with the prescription of pancreatic enzymes—which only 27% of them received [3]. Given the incidence of PEI in chronic pancreatitis and pancreatic cancer, at least 50% will be in need for PERT [4]. These data corroborate smaller but more detailed studies from the United States where PERT was given correctly in 30% [5] and Europe with 60%–80% of the patients with chronic pancreatitis receiving proper PERT [6, 7]. This short paper conveys an important message as it puts a flashlight on a deficiency of our own doing: treating our patients right. As solid as these data are, from this height, some shortcomings are noteworthy: although chronic pancreatitis and pancreatic cancer are the two major diseases with PEI and hence prime indications for PERT, other conditions exist such as diabetes mellitus [8] and the elderly [9]. Admittedly, the frequency of correctly identifying and treating PEI will be even lower here. One also might have looked back in this national database from the enzyme prescriptions to the linked diagnoses to learn about other indications for PERT. Finally, the incidence of chronic pancreatitis and pancreatic cancer based on the reported ICD codes seems rather low. As PEI in chronic pancreatitis and pancreatic cancer is on the rise [10], the study by Kumar should be taken as a call for action for all those diagnosed with a pancreatic disease to search for PEI and then treat it according to the guidelines [1, 2]. For those not seeing these patients on a daily basis, the United European Gastroenterology (UEG) has provided an app free of charge containing more than 30 gastroenterology-related guidelines, including the one on PEI and PERT (see https://ueg.eu/quality-of-care/search-guidelines/gi-guidelines-app). The author declares no conflict of interest.

The aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP). Cross-sectional study of children <19 years with ARP or CP, at enrollment into the INSPPIRE cohort. We categorized patients as opioid "frequent use" (daily/weekly) or "nonfrequent use" (monthly or less, or no opioids), based on patient and parent self-report. Of 427 children with ARP or CP, 17% reported frequent opioid use. More children with CP (65%) reported frequent opioid use than with ARP (41%, P = 0.0002). In multivariate analysis, frequent opioid use was associated with older age at diagnosis (odds ratio [OR] 1.67 per 5 years, 95% confidence interval [CI] 1.13-2.47, P = 0.01), exocrine insufficiency (OR 2.44, 95% CI 1.13-5.24, P = 0.02), constant/severe pain (OR 4.14, 95% CI 2.06-8.34, P < 0.0001), and higher average pain impact score across all 6 functional domains (OR 1.62 per 1-point increase, 95% CI 1.28-2.06, P < 0.0001). Children with frequent opioid use also reported more missed school days, hospitalizations, and emergency room visits in the past year than children with no frequent use (P < 0.0002 for each). Participants in the US West and Midwest accounted for 83% of frequent opioid users but only 56% of the total cohort. In children with CP or ARP, frequent opioid use is associated with constant pain, more healthcare use, and higher levels of pain interference with functioning. Longitudinal and prospective research is needed to identify risk factors for frequent opioid use and to evaluate nonopioid interventions for reducing pain and disability in these children.

Objective:Chronic pancreatitis (CP) is the most common cause of pancreatic exocrine insufficiency (PEI). Management of PEI due to CP is achieved through lifelong treatment with pancreatic enzyme replacement therapy (PERT). To the authors’ knowledge, no cost-effectiveness analysis on the benefit of PERT in CP patients with PEI has been performed to date. The objective of this analysis was to examine the cost-effectiveness of Creon (pancreatin minimicrospheres [MMS]), one of the main PERTs available in Poland, in treating patients with CP-related PEI.Methods:The cost-effectiveness of pancreatin MMS in the treatment of patients with CP-related PEI vs no PERT treatment was estimated using a decision analysis based on clinical data from relevant studies. The model horizon was 20 years. Main outcomes included the percentage of patients with controlled PEI, survival, total medical costs, number of quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER). All costs were analysed from the Polish payer perspective.Results:The model included clinical data from 176 patients treated in five pancreatin MMS randomized trials. Treatment with pancreatin MMS resulted in a considerably higher proportion of patients with controlled PEI compared to those not treated with any PERT. Over a horizon of 20 years, the total treatment cost and the ICER for pancreatin MMS was €8223 and €6312 per QALY, respectively.Limitations:Important limitations include the lack of long-term and comparative clinical data available. The use of ‘no PERT treatment’ as a comparator against pancreatin MMS treatment may not accurately reflect current practice in Poland.Conclusions:Treatment of CP-related PEI with pancreatin MMS is cost-effective from a Polish payer perspective, with an ICER below the accepted ‘willingness to pay’ threshold of 3-times gross domestic product (GDP) per capita. These results are likely to apply to other European countries.

Pancreatic exocrine insufficiency (PEI), defined as a secretion of pancreatic enzymes and bicarbonate insufficient to maintain a normal digestion, is a frequent but frequently underdiagnosed and undertreated condition. PEI may be secondary to different pancreatic diseases and extrapancreatic conditions. Recent data support the high clinical relevance of PEI and its treatment. Together with symptoms of maldigestion, PEI is associated with nutritional deficiencies leading to osteoporosis, low-trauma fractures, sarcopenia and increased mortality. No single widely available test allows to diagnose PEI accurately. Diagnosis of PEI requires the evaluation of symptoms, nutritional markers and a noninvasive pancreatic function test in the appropriate clinical context. Pancreatic enzyme replacement therapy (PERT) improves digestion, symptoms, nutritional status and quality of life of patients with PEI. In addition, PERT is associated with a longer survival in patients with unresectable pancreatic cancer and after surgery for pancreatic cancer or chronic pancreatitis. Awareness of PEI in different clinical conditions is required. Nutritional advice and appropriate PERT are mandatory to reduce the morbidity and mortality associated with PEI. Further studies on the clinical impact of PEI and its treatment are needed, especially in diseases other than chronic pancreatitis and cystic fibrosis.

Introduction: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. Methods: A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. Results: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. Conclusions: This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes. Introduction: Exocrine pancreatic insufficiency (EPI) is caused by multiple clinical conditions such as cystic fibrosis and chronic pancreatitis (CP). Standard management of EPI includes pancreatic enzyme replacement therapy (PERT) along with consultation with a dietitian. While PERTs have been on the market for several decades, newer publications on their clinical efficacy and safety raised the need for a comprehensive review of the literature. We aimed to identify the available evidence on the clinical efficacy and safety of treatments for EPI to understand the current treatment landscape and unmet need in patients with EPI. Methods: A systematic literature review (SLR) was conducted in Embase, Medline, and Evidence-Based Medicine databases from 2010 to 2022; conference proceedings from 2020 to 2022 were also searched. Articles were screened independently by two reviewers at abstract and full-text stage against predefined eligibility criteria. Results: We identified 26 journal publications and two conference abstracts, reporting on 22 randomized control trials, four observational studies, and two single-arm interventional studies. The most reported treatment was pancrelipase, specifically Creon® (n = 12). Fourteen studies reported coefficient of fat absorption (CFA) results. Across studies, patients experienced a considerable increase in CFA post-initiation of treatment regardless of intervention or timepoint. Mean change in CFA ranged from 7.5% in patients with CP who received placebo to 36% in patients with CP treated with Creon®. Ten studies reported coefficient of nitrogen absorption (CNA). Where reported, pancrelipase (including Creon®) increased CNA levels in EPI patients compared to placebo. Only one study compared PERT brands head-to-head: no significant differences were reported in the CNA-72 h values (Creon® 82.0% [SE: 1.2] vs. Zenpep® 80.9% [SE: 1.2]). Loss of body weight and low body mass index (BMI) are important features of EPI. Overall, treatment with PERT increased BMI and body weight, or limited their decline, with increases ranging from 0.1 to 6.1 kg. Based on the 18 studies that reported safety outcomes, PERT was considered safe and well tolerated. Conclusions: This SLR confirmed that PERT is an effective and tolerable treatment option for patients with EPI. However, nutritional parameters and health-related quality of life data were sparsely reported, and future clinical trials should look to incorporate these data given their importance in clinical practice and patient outcomes.

Patients with chronic pancreatitis or pancreatic cancer commonly develop exocrine pancreatic insufficiency, and may not be adequately treated with pancreatic enzyme replacement therapy (PERT). To estimate the frequency of diagnostic testing for exocrine insufficiency, and appropriate use of PERT, in a commercially insured population in the US. We utilised a nationally representative administrative database representing 48.67 million individuals in over 80 US healthcare plans to assess testing for and treatment of exocrine insufficiency in patients who received a diagnosis of chronic pancreatitis (n=37061) or pancreatic cancer (n=32461) from 2001to 2013. We identified the details of any testing for exocrine insufficiency and PERT use. We defined appropriate PERT use as a dosage of ≥120000 USP units of lipase daily. Multiple logistic regression was used to identify predictors of appropriate use of PERT. In patients with chronic pancreatitis, 6.5% had any testing for exocrine insufficiency, 30.4% filled a prescription for PERT, and 8.5% were prescribed an adequate dose. In those with pancreatic cancer, 1.9% had testing for exocrine insufficiency, 21.9% filled a prescription for PERT, and 5.5% were prescribed an adequate dose. Number of comorbidities, testing for exocrine insufficiency, pancreatic surgery and duration of enrolment were independent predictors for use and appropriate dosing. Testing for exocrine insufficiency, and appropriate dosing of PERT in patients with chronic pancreatitis or pancreatic cancer, is infrequent and inconsistent in an insured US population. Efforts are needed to educate medical providers on the best practices for managing exocrine pancreatic insufficiency in these patients.

Pancreatic exocrine insufficiency (PEI) is a common complication of chronic pancreatitis. However, little is known about the natural course of PEI and the effect of pancreatic enzyme replacement therapy on symptoms. The aim of this study was to evaluate the natural course and treatment of PEI in a nationwide cohort of patients with chronic pancreatitis. Patients with chronic pancreatitis were selected from the multicenter Dutch Chronic Pancreatitis Registry. Patients were classified in 3 groups: definite PEI, potential PEI, and no PEI. Definite PEI and no PEI were compared regarding the course of disease, symptoms, treatment, and quality of life. Nine hundred eighty-seven patients were included from 29 centers, of which 304 patients (31%) had definite PEI; 451 (46%), potentially PEI; and 232 (24%), no PEI. Patients with definite PEI had significantly more malabsorption symptoms, a lower body mass index, and aberrant defecation. Lowered quality of life was not independently associated with PEI. Of the PEI patients using pancreatic enzyme replacement therapy, 47% still reported steatorrhea. Pancreatic exocrine insufficiency is associated with malabsorption symptoms and a lower body mass index. Some form of pancreatic enzyme replacement therapy is reasonably effective in alleviating malabsorption symptoms, but improvement of treatment is needed.

The aim of this study was to study the prevalence of exocrine pancreas insufficiency (EPI) at a population level and the subsequent risk of pancreatic ductal adenocarcinoma (PDAC). Using TriNetX (a database of over 79 million US residents), we included patients ≥18 years with EPI (identified via ICD-10 codes) and continuous follow-up from 2016-2022. Patients with prior pancreas resection and PDAC before an EPI diagnosis were excluded. The primary outcome was EPI prevalence. Secondary outcomes included imaging utilization, PDAC risk, and pancreatic enzyme replacement therapy (PERT) utilization. We performed 1:1 propensity score matching (PSM) of patients with EPI versus patients without an EPI diagnosis. The population prevalence of EPI was 0.8% (n = 24,080) with a mean age of 55.6 years. After PSM, PDAC risk among patients with EPI was twice as high compared with patients without EPI (aHR, 1.97; 95% CI, 1.66-2.36). This risk persisted even after excluding patients with a history of acute or chronic pancreatitis (adjusted odds ratio, 4.25; 95% CI, 2.99-6.04). Only 58% (n = 13, 390) of patients with EPI received PERT. No difference was observed in PDAC risk between patients with EPI on PERT and those not on PERT (aHR, 1.10; 95% CI, 0.95-1.26; P = 0.17). Despite a low prevalence, patients with EPI may have a higher risk of PDAC, and majority with EPI were not on PERT. PERT did not impact incident PDAC risk after an EPI diagnosis.

Chronic Pancreatitis and Bone Disease

Pancreatic exocrine insufficiency is an important cause of maldigestion and a major complication in chronic pancreatitis. Normal digestion requires adequate stimulation of pancreatic secretion, sufficient production of digestive enzymes by pancreatic acinar cells, a pancreatic duct system without significant outflow obstruction and adequate mixing of the pancreatic juice with ingested food. Failure in any of these steps may result in pancreatic exocrine insufficiency, which leads to steatorrhea, weight loss and malnutrition-related complications, such as osteoporosis. Methods evaluating digestion, such as fecal fat quantification and the (13)C-mixed triglycerides test, are the most accurate tests for pancreatic exocrine insufficiency, but the probability of the diagnosis can also be estimated based on symptoms, signs of malnutrition in blood tests, fecal elastase 1 levels and signs of morphologically severe chronic pancreatitis on imaging. Treatment for pancreatic exocrine insufficiency includes support to stop smoking and alcohol consumption, dietary consultation, enzyme replacement therapy and a structured follow-up of nutritional status and the effect of treatment. Pancreatic enzyme replacement therapy is administered in the form of enteric-coated minimicrospheres during meals. The dose should be in proportion to the fat content of the meal, usually 40-50000 lipase units per main meal, and half the dose is required for a snack. In cases that do not respond to initial treatment, the doses can be doubled, and proton inhibitors can be added to the treatment. This review focuses on current concepts of the diagnosis and treatment of pancreatic exocrine insufficiency.

ObjectivesThis study aimed to provide patients insights on the management of exocrine pancreatic insufficiency (EPI) with pancreatic enzyme replacement therapy (PERT).Materials and MethodsA survey of 75 members of Inspire's Pancreatitis or Pancreatic Cancer Support communities was conducted. Eligibility included having EPI secondary to chronic pancreatitis, pancreatic cancer, pancreatic surgery, or acute pancreatitis, and current/past PERT experience.ResultsPatients were 73% female, 57% aged 50 to 69 years, and 85% White, with PERT prescribed by a gastroenterologist/pancreatologist for 64%. Only approximately half of respondents agreed that their healthcare provider provided detailed information about EPI (54%) or how PERT works to treat EPI (56%). Most respondents (83%) reported searching for information about EPI, 56% were taking PERT solely before or after eating, 36% reported taking suboptimal PERT doses, and 39% reported no follow-up. In addition, 24% decreased their PERT dosage without consulting their physician, and 21% reported purposely skipping PERT.ConclusionsThis study reveals potential barriers to effective treatment of EPI with PERT, including lack of patient education, mainly how and when to take PERT, gaps in appropriate dosing, and lack of patient follow-up. Continued focus on patient and provider education is essential to address these gaps and optimize the treatment of EPI.

Exocrine pancreatic insufficiency (EPI) is associated with conditions including cystic fibrosis (CF), chronic pancreatitis (CP), and pancreatic surgery (PS). The symptoms include maldigestion, malnutrition, weight loss, flatulence, and steatorrhea. Pancreatic enzyme replacement therapy (PERT) is the standard treatment for EPI; it is regulated in many countries and most recently in the USA following a US FDA mandate for all PERT manufacturers to submit new drug applications. Pancrelipase delayed-release capsules (CREON®, Abbott, Marietta, GA, USA) have been available in Europe since 1984 and in the USA since 1987; a new formulation was the first PERT to gain approval in the USA in 2009. The efficacy and safety of CREON have been demonstrated in double-blind, randomized, placebo-controlled trials in patients with CF aged ≥7 years and in patients with CP or post-PS. The data consistently demonstrate significantly better fat and nitrogen absorption with CREON versus placebo, and improvements in clinical symptoms, stool frequency, and body weight. Additionally, efficacy and safety of CREON have been shown in open-label studies in young children with CF (aged 1 month to 6 years), with control of fat malabsorption and control of clinical symptoms. The most commonly reported adverse events (AEs) with PERT are gastrointestinal disorders and allergic skin reactions. In clinical studies, CREON was well tolerated with very few withdrawals due to AEs and a low frequency of AEs judged treatment related, regardless of patient age. To further support the known safety profile of PERT, all manufacturers are required to investigate risk factors for fibrosing colonopathy, a rare gastrointestinal complication of CF, and the theoretical risk of viral transmission from porcine-derived PERT products. Together, the clinical study data and wealth of clinical experience suggest that CREON is effective and safe in patients with EPI regardless of etiology, with a very favorable risk-benefit profile.

Su1888 Pancreatic Enzyme Replacement Therapy in Chronic Pancreatitis and Pancreatic Cancer- Are We Getting It Right?