Exocrine pancreatic insufficiency (EPI) is characterized by the maldigestion of food and malabsorption of nutrients because of inadequate intraduodenal pancreatic exocrine enzyme delivery.1–3 1,4–6 1,7–9 2,4,6,9–11 6 10 7 12 7,11
Pancreatic enzyme replacement therapy (PERT) with pancrelipase (PL) is the standard treatment for EPI in patients with CP and T2D and aims to normalize digestion and nutritional status.3,13,14 6 15,16 6,7,17 15
Although the efficacy and tolerability of PERT for the management of EPI have been demonstrated in clinical trials, no studies have assessed real-world longitudinal symptom outcomes in patients with CP or T2D. The objective of this study was to evaluate real-world GI symptom profiles over time in PL-treated patients with EPI symptoms and CP or T2D in the United States (US). The impact of treatment compliance and prescribing health care professional (HCP) specialty on the effectiveness of PERT was also assessed.
MATERIALS AND METHODS
Patient Demographics
This was a retrospective study using real-world data. Medical claims data were obtained from the Decision Resources Group Real-World Evidence Data Repository US database, which links medical claims, prescription claims, and electronic health records to provide longitudinal patient-level data. These data include patient records with tests ordered, test results, diagnoses, comorbidities, medications, therapies, and patient demographics. The repository represents approximately 98% of US health plans and provides insight into individual health plans.18
Patients included in this analysis were 18 years and older and received PL (Zenpep, Nestlé Health Science, Bridgewater, NJ) at an index date between August 1, 2015, and June 30, 2020. Patient pre-index characteristics and comorbidities were obtained from data reaching back to 2014, if necessary (Table 1 ). Patients were stratified into mutually exclusive CP and T2D cohorts using relevant International Classification of Diseases, Tenth Revision, Clinical Modification diagnosis codes and Zenpep national drug codes. To ensure sufficient historical data and continuous coverage both pre- and post-index, patients must have presented with at least 1 claim within 12 months before their initial Zenpep prescription and at least 1 claim every 6 months after the initial Zenpep prescription (up to 18 months). Outcomes assessed included patient demographics, clinical characteristics, prescribing HCP specialty (gastroenterology or general practitioner/internal medicine, including endocrinologists), medication compliance, and treatment effectiveness.
TABLE 1 -
Patient Demographics (CP and T2D Cohorts)
CP, n (%) (n = 3215)
T2D, n (%) (n = 7441)
Age, y
18–24
48 (1)
73 (1)
25–34
195 (6)
182 (2)
35–44
374 (12)
317 (4)
45–54
671 (21)
705 (9)
55–64
882 (27)
1493 (20)
≥65
1045 (33)
4671 (63)
Sex
Male
1231 (38)
2834 (38)
Female
1984 (62)
4607 (62)
Region
Midwest
884 (27)
1311 (18)
Northeast
494 (15)
2129 (29)
South
1138 (35)
2587 (35)
West
699 (22)
1410 (19)
Other
0 (0)
4 (0)
Payer channel*
Commercial
1975 (61)
2511 (34)
Other
74 (2)
100 (1)
Medicaid
62 (2)
160 (2)
Medicare + Medicare Advantage
1104 (34)
4670 (63)
*Based on first claim present with valid payer information in study period. Other payers include payer channels such as Veterans Affairs and other government.
Statistical Analyses
Descriptive statistical analyses were carried out for all study variables. Univariate analyses were conducted using t tests and chi-square tests for continuous and discrete variables respectively (α = .05 level of significance). Gastrointestinal symptoms were assessed at 6, 12, and 18 months post-index versus baseline (baseline was assessed up to 1 year pre-index). Univariate statistics were calculated for demographic and payer characteristics, underlying health conditions, and accompanying EPI diagnostic tests at baseline. The proportion of patients with symptom events, stratified by prescribing HCP specialty and medication compliance [based on treatment duration from first to last prescription date; high (>270 days) and low (<90 days)], were used to determine the effectiveness of treatment at each time point.
RESULTS
Patient Characteristics
The study identified 10,656 patients with CP (n = 3215) or T2D (n = 7441) treated with PL during the post-index period (PIP). The mean (SD) age of patients with CP and T2D was 57 (15) and 67 (14), respectively. Most patients were 55 years and older [60% (n = 1927) and 83% (n = 6164) of patients with CP and T2D, respectively]. Higher proportions of females were observed in both cohorts (Table 1 ). Almost half of all patients had a comorbidity related to EPI (48% and 45% of patients with CP and T2D, respectively), with gastroenteritis and colitis being the most common [CP (29%) and T2D (24%)], followed by irritable bowel syndrome [CP (18%) and T2D (16%)] (Fig. 1 ). Patients with T2D had a higher mean Charlson Comorbidity Index score than those with CP (T2D = 4 vs CP = 2). All US regions were represented across both disease cohorts.
FIGURE 1: Patient distribution by EPI-related comorbidities (1 year pre-index). Baseline is evaluated up to 1 year pre-index.
Most patients in the CP cohort were covered by commercial payers (61%), and a smaller proportion were covered by Medicare/Medicare Advantage (34%) (Table 1 ). Conversely, most patients in the T2D cohort were covered by Medicare/Medicare Advantage (63%), and a smaller proportion were covered by commercial payers (34%). Prescribing physician specialties for both cohorts are presented in Table 2 and Supplemental Table 1, https://links.lww.com/MPA/A1000
TABLE 2 -
Prescribing Physician Specialty (CP and T2D Cohorts)
Prescribing Physician Specialty
CP, % (n = 3215)
T2D, % (n = 7441)
Gastroenterology
38
29
General practitioner
21
24
Internal medicine
17
22
Endocrinology
0
1
Oncology
1
3
Other
22
21
Treatment Effectiveness in Patients With CP
Among patients with CP (n = 3215), abdominal pain was the most common symptom at baseline (evaluated as up to 1 year pre-index), reported by 30% of individuals. A smaller proportion of patients experienced nausea and vomiting, diarrhea and steatorrhea, and gas and bloating at baseline (10%, 8%, and 1%, respectively). Compared with baseline, significant and sustained reductions in all GI symptoms were observed after PL treatment over the 18-month study period (P < 0.001 across symptoms) (Fig. 2 and Supplemental Table 2, https://links.lww.com/MPA/A1000 P < 0.03) reduction in all reported GI symptoms at 6, 12, and 18 months after initiation of PL, compared with baseline, regardless of whether prescriber specialty was gastroenterology (n = 1237) or general practitioner/internal medicine (n = 1233) (Fig. 3 and Supplemental Table 2, https://links.lww.com/MPA/A1000
FIGURE 2: Reduction in reported GI symptoms over 18 months (CP cohort, n = 3215). Baseline is evaluated up to 1 year pre-index.
FIGURE 3: Treatment effectiveness by prescribing HCP specialty (CP cohort). Baseline is evaluated up to 1 year pre-index. General practitioner/internal medicine includes endocrinologists.
Changes in GI symptoms were also assessed for patients stratified by treatment compliance over the PIP. A significantly smaller proportion of patients who complied with PL treatment for more than 270 days (n = 1553) over the PIP reported abdominal pain (P < 0.001) or nausea and vomiting (P < 0.05) at 6, 12, and 18 months compared with patients who received PL treatment for less than 90 days (n = 1115) (Fig. 4 and Supplemental Table 3, https://links.lww.com/MPA/A1000 P < 0.001), nausea and vomiting (P < 0.001), and diarrhea and steatorrhea (P < 0.05) were significantly higher in the low medication compliance cohort than in the high medication compliance cohort.
FIGURE 4: Treatment effectiveness by medication compliance (CP cohort). Baseline is evaluated up to 1 year pre-index.
The following combinations of symptoms (diagnosed on the same day) were also analyzed: abdominal pain with nausea and vomiting, abdominal pain with diarrhea, diarrhea with nausea and vomiting, and abdominal pain with diarrhea and nausea and vomiting. Of these, abdominal pain with nausea and vomiting was the most common symptom combination at baseline, reported by 8% of patients (Fig. 5 and Supplemental Table 2, https://links.lww.com/MPA/A1000 P < 0.001).
FIGURE 5: Reduction in combined GI symptoms over 18 months (CP cohort). Baseline is evaluated up to 1 year pre-index.
Treatment Effectiveness in Patients With T2D
Among patients with T2D (n = 7441), abdominal pain was the most common symptom at baseline, reported by 13% of individuals. The proportion of patients with nausea and vomiting, diarrhea and steatorrhea, and gas and bloating at baseline was 4%, 9%, and 3%, respectively. Compared with baseline, significant and sustained reductions in all GI symptoms were observed after PL treatment over the 18-month study period (P < 0.001 across symptoms) (Fig. 6 and Supplemental Table 4, https://links.lww.com/MPA/A1000 Fig. 7 and Supplemental Table 4, https://links.lww.com/MPA/A1000 P < 0.001).
FIGURE 6: Reduction in reported GI symptoms over 18 months (T2D cohort, n = 7441). Baseline is evaluated up to 1 year pre-index.
FIGURE 7: Treatment effectiveness by prescribing HCP specialty (T2D cohort). Baseline is evaluated up to 1 year pre-index. General practitioner/internal medicine includes endocrinologists.
Patients with T2D in the low medication compliance (<90 days) cohort were approximately twice as likely to experience GI symptoms at baseline and over the PIP compared with those in the high medication compliance (>270 days) cohort (Fig. 8 and Supplemental Table 5, https://links.lww.com/MPA/A1000 P < 0.001) or diarrhea and steatorrhea (P < 0.05) at 6, 12, and 18 months compared with patients who received PL treatment for less than 90 days (n = 2959). At baseline, the proportions of patients reporting various GI symptoms were significantly higher in the low medication compliance (<90 days) cohort than in the high medication compliance (>270 days) cohort (P < 0.001).
FIGURE 8: Treatment effectiveness by medication compliance (T2D cohort). Baseline is evaluated up to 1 year pre-index.
The GI symptom combinations described for the CP cohort were also analyzed for the T2D cohort. The most common symptom combinations were abdominal pain with diarrhea and abdominal pain with nausea and vomiting, both reported by 2% of patients (Fig. 9 and Supplemental Table 4, https://links.lww.com/MPA/A1000 P < 0.001).
FIGURE 9: Reduction in combined GI symptoms over 18 months (T2D cohort). Baseline is evaluated up to 1 year pre-index.
DISCUSSION
This large, retrospective real-world study of US claims data in patients with CP or T2D evaluated the impact of PL-based PERT on EPI-related symptoms. Treatment with PL resulted in significant and sustained reductions in GI symptoms (abdominal pain, nausea and vomiting, diarrhea and steatorrhea, and gas and bloating) over the 18-month study period, with greater PL compliance leading to improved symptom profiles. Among patients with CP, abdominal pain and nausea and vomiting were reported for a significantly smaller proportion of patients who complied with PL treatment for more than 270 days over the PIP compared with those who used PL for less than 90 days. Within the T2D cohort, abdominal pain and diarrhea and steatorrhea were experienced by a significantly smaller proportion of patients who complied with PL treatment for more than 270 days versus less than 90 days. These findings highlight the positive impact of PL on GI symptoms and the importance of patient compliance on the effectiveness of PERT in both patients with CP and T2D.
Data from RCTs demonstrate the tolerability and efficacy of PL-based PERT for the management of EPI-related GI symptoms in patients with CP or T2D.6,15,19
In patients with T2D, a larger proportion of patients who were prescribed treatment by gastroenterologists reported GI symptoms than those prescribed by general practitioners or internal medicine HCPs. This may reflect the fact that patients experiencing more severe EPI are referred to and treated by gastroenterology specialists. In contrast, a comparable proportion of patients with CP reported GI symptoms in the gastroenterology and general practitioner/internal medicine groups. In both CP and T2D cohorts, significant and sustained improvements in symptom profiles were observed for both prescribing HCP groups studied, indicating that prescribing specialty does not influence treatment effectiveness.
In common with investigations of this type, this study has limitations. The data accessed were limited to those present in the Decision Resources Group Real-World Evidence Data Repository US database. Real-world databases obtained from routine clinical practice are subject to missing and erroneous data, coding imperfections, a lack of standardization of clinical measures, variations between clinical testing centers, and measurements that are taken with varying periodicity.20 20
Despite evidence of efficacy from RCTs, there are limited data on the effectiveness of PL-based PERT in routine clinical practice. This analysis of real-world data provides valuable insight on the effectiveness of PL-based PERT for improving EPI-related symptoms among patients with CP or T2D and may be used to develop optimal management strategies for these populations. Notably, the effectiveness of PL treatment was found to be similar regardless of prescribing specialty, highlighting the applicability of PL-based PERT for the management of EPI among a broad range of HCPs.
This real-world retrospective study demonstrates that PL-based PERT significantly reduces GI symptoms in patients with CP or T2D, with greater compliance associated with improved symptom profiles. Treatment effectiveness was similar regardless of whether PL was prescribed by gastroenterologists or general practitioners/internal medicine specialists, indicating that prescribing specialty does not impact treatment effectiveness. These results may inform clinician decision-making and support the optimal management of patients with EPI-related symptoms in CP and T2D.
ACKNOWLEDGMENTS
The authors acknowledge Richard Massey and Chizoba Esio-Bassey (Clarivate) for medical writing support.
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