# Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study

Laure Alexandre-Heymann, Fetta Yaker, Pierre Bel Lassen, Danièle

Dubois-Laforgue, Etienne Larger

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## ► To cite this version:

Laure Alexandre-Heymann, Fetta Yaker, Pierre Bel Lassen, Danièle Dubois-Laforgue, Etienne Larger. Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study. Diabetology and Metabolic Syndrome, 2024, 16 (1), pp.39-50.

10.1186/s13098-024-01265-4 hal-04586564

HAL Id: hal-04586564

https://u-paris.hal.science/hal-04586564

Submitted on 24 May 2024

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# Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study

Laure Alexandre-Heymann, Fetta Yaker, Pierre Bel Lassen, Danièle

Dubois-Laforgue, Etienne Larger

► To cite this version:

Laure Alexandre-Heymann, Fetta Yaker, Pierre Bel Lassen, Danièle Dubois-Laforgue, Etienne Larger. Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study. Diabetology and Metabolic Syndrome, 2024, 16 (1), pp.39-10.1186/s13098-024-01265-4. http://dx.doi.org/10.1186/s13098-024-01265-4

HAL Id: hal-04586564

https://u-paris.hal.science/hal-04586564v1

Submitted on 24 May 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

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Distributed under a Creative Commons Attribution 4.0 International License
RESEARCH

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# Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study

Laure Alexandre-Heymann<sup>1,2*</sup>, Fetta Yaker<sup>1</sup>, Pierre Bel Lassen<sup>3,4</sup>, Danièle Dubois-Laforgue<sup>1,2</sup> and Etienne Larger<sup>1,2</sup>

**Abstract**

**Background** Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause.

**Methods** In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI).

**Results** 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups.

**Conclusions** PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders.

*Trial registration* Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047

**Keywords** Fecal elastase, Pancreatic enzyme replacement therapy, Exocrine pancreatic insufficiency, Diabetes

<footnote>*Correspondence:
Laure Alexandre-Heymann
erualex@gmail.com
Full list of author information is available at the end of the article</footnote>
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# Pancreatic enzyme replacement therapy in subjects with exocrine pancreatic insufficiency and diabetes mellitus: a real-life, case-control study

Laure Alexandre-Heymann<sup>1,2*</sup>, Fetta Yaker<sup>1</sup>, Pierre Bel Lassen<sup>3,4</sup>, Danièle Dubois-Laforgue<sup>1,2</sup> and Etienne Larger<sup>1,2</sup>

**Abstract**

**Background** Exocrine pancreatic insufficiency (EPI) can be associated with all types of diabetes. Pancreatic enzyme replacement therapy (PERT) has short and long-term benefits in subjects with EPI, but its effects on diabetes control are uncertain. We aimed to study the effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause.

**Methods** In this retrospective study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a fecal elastase-1 concentration dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c and body mass index (BMI).

**Results** 48 subjects were included in each group. Overall, PERT did not have any significant effect on hypoglycemia frequency or severity, but hypoglycemia frequency tended to decrease in subjects with chronic pancreatitis. While 19% of subjects experienced mild hyperglycemia after PERT initiation, we did not report any keto-acidosis or any other severe adverse event. Gastro-intestinal disorders improved in 80% of subjects treated with PERT, versus in 20% of control subjects (p = 0.02). Gastro-intestinal disorders improved in 87% of subjects with recommended dosage of PERT, versus in 50% of subjects with underdosage (NS). HbA1c and BMI evolution did not differ between the groups.

**Conclusions** PERT initiation is safe in subjects with diabetes and EPI. It does not globally decrease hypoglycemia severity of frequency, but is associated with a decrease in gastro-intestinal disorders.

*Trial registration* Retrospectively registered. The database was registered with the Commission Nationale Informatique et Libertés (CNIL), registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number: AAA-2023-09047

**Keywords** Fecal elastase, Pancreatic enzyme replacement therapy, Exocrine pancreatic insufficiency, Diabetes

<footnote>*Correspondence:
Laure Alexandre-Heymann
erualex@gmail.com
Full list of author information is available at the end of the article</footnote>
## Background

Exocrine pancreatic insufficiency (EPI) is a hallmark of diabetes mellitus secondary to pancreatic diseases, also known as pancreatogenic diabetes. This type of diabetes can affect subjects with acute pancreatitis [1], chronic pancreatitis (CP), pancreatic cancer, or cystic fibrosis. Pancreatogenic diabetes is often misdiagnosed with either type 1 (T1D) or type 2 diabetes (T2D) and could represent up to 10% of the causes of diabetes, at least among hospitalized subjects [2]. However, clinically relevant EPI can also be observed in 11 to 30% of subjects with T1D [3, 4], 8% of subjects with T2D [5], and in subjects with several types of Maturity Onset Diabetes of the Young (MODY) [6].

It is important to screen for EPI in subjects with diabetes and suggestive symptoms, e.g. abdominal pain, weight loss, maldigestion, or frequent episodes of hypoglycemia. Indeed, EPI associates with complications such as weight loss, diarrhea and steatorrhea, malnutrition [7], osteoporosis, and increased cardiovascular risk [8], and many studies have shown that treating EPI with pancreatic enzyme replacement therapy (PERT) has both short- and long-term benefits [9]. On the short- to medium-term, PERT improves fat and nitrogen absorption [10], induces weight gain [11], and decreases gastro-intestinal symptoms frequency and severity [12, 13]. On the long-term, PERT improves quality of life [14, 15], decreases the risk of bone fractures [16], and improves survival in subjects with CP or with pancreatic cancer [17, 18].

Subjects with pancreatogenic diabetes may develop “brittle diabetes” with rapid glycemic shifts and risk of severe hypoglycemia and hyperglycemia [19–21]. However, only a few studies have been conducted on the effects of PERT on glycemic control: PERT has been shown to improve glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) secretion [22] and is thus expected to affect gastric emptying and postprandial blood glucose concentration. Indeed, in the context of cystic fibrosis, studies showed that PERT normalized GLP-1 secretion, slowed gastric emptying, and decreased postprandial blood glucose without completely normalizing it [23, 24]. In another study performed on subjects with fibrocalculated pancreatitis, PERT was associated with lower HbA1c and postprandial plasma glucose [25]. However, studies performed on small numbers of subjects with CP or T2D did not show any effect of PERT on post-prandial blood glucose, C-peptide secretion or on gastric emptying [26–28]. Conversely, PERT could also worsen glycemic control by increasing nutrients absorption. In one study performed on 18 subjects with CP and diabetes, one subject had major difficulties to attain acceptable glycemic control and one developed ketoacidosis after PERT initiation,

while two subjects experienced severe hypoglycemia after ceasing PERT [29]. However, these complications were not confirmed in other studies [10, 26]. A randomized, versus placebo study in subjects with insulin-treated diabetes mellitus and EPI showed that PERT could be used safely, and reduced the frequency of mild and moderate hypoglycemia [30].

Therefore, we aimed to study the real-life effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. In this study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a relatively low fecal elastase-1 concentration (FEC) dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c, body mass index (BMI), and on overall diabetes management.

## Methods

### Subjects

We conducted a retrospective study comparing participants with diabetes with or without PERT initiation. It was conducted at a tertiary referral center (the Diabetology Department of Cochin Hospital, Paris).

All subjects followed in our Diabetology Department who had PERT initiation between September 2013 and September 2022, and who were diagnosed with diabetes at least 3 months before PERT initiation, and who had severe EPI as defined by a FEC < 100 µg/g of stool, and who had at least one consultation in the department within the 2 years following PERT initiation were included in the PERT group. Subjects were defined as having PERT initiation if they received a prescription of pancreatin gastro-resistant capsules for the first time. In France, pancreatin is sold under 2 brand names: CREON® (Viatris Santé, France) or EUROBIOL® (Mayoly Spindler, France).

For the control group, we selected subjects followed in our Diabetology Department who did not receive PERT, matched on age and gender with the subjects from the PERT group (1:1). We selected subjects in whom a FEC dosage was performed between January 2016 and September 2022 with a relatively low result (<300 µg/g), in order to get clinically similar subjects to the PERT group. To be included, they also had to be diagnosed with diabetes at least 3 months before FEC dosage and to have at least one consultation in the department within the 2 years following FEC dosage.

### Materials and methods

We extracted all biological, radiological and clinical data from the subjects’ electronic medical records.
## Background

Exocrine pancreatic insufficiency (EPI) is a hallmark of diabetes mellitus secondary to pancreatic diseases, also known as pancreatogenic diabetes. This type of diabetes can affect subjects with acute pancreatitis [1], chronic pancreatitis (CP), pancreatic cancer, or cystic fibrosis. Pancreatogenic diabetes is often misdiagnosed with either type 1 (T1D) or type 2 diabetes (T2D) and could represent up to 10% of the causes of diabetes, at least among hospitalized subjects [2]. However, clinically relevant EPI can also be observed in 11 to 30% of subjects with T1D [3, 4], 8% of subjects with T2D [5], and in subjects with several types of Maturity Onset Diabetes of the Young (MODY) [6].

It is important to screen for EPI in subjects with diabetes and suggestive symptoms, e.g. abdominal pain, weight loss, maldigestion, or frequent episodes of hypoglycemia. Indeed, EPI associates with complications such as weight loss, diarrhea and steatorrhea, malnutrition [7], osteoporosis, and increased cardiovascular risk [8], and many studies have shown that treating EPI with pancreatic enzyme replacement therapy (PERT) has both short- and long-term benefits [9]. On the short- to medium-term, PERT improves fat and nitrogen absorption [10], induces weight gain [11], and decreases gastro-intestinal symptoms frequency and severity [12, 13]. On the long-term, PERT improves quality of life [14, 15], decreases the risk of bone fractures [16], and improves survival in subjects with CP or with pancreatic cancer [17, 18].

Subjects with pancreatogenic diabetes may develop “brittle diabetes” with rapid glycemic shifts and risk of severe hypoglycemia and hyperglycemia [19–21]. However, only a few studies have been conducted on the effects of PERT on glycemic control: PERT has been shown to improve glucagon-like peptide-1 (GLP1) and glucose-dependent insulinotropic polypeptide (GIP) secretion [22] and is thus expected to affect gastric emptying and postprandial blood glucose concentration. Indeed, in the context of cystic fibrosis, studies showed that PERT normalized GLP-1 secretion, slowed gastric emptying, and decreased postprandial blood glucose without completely normalizing it [23, 24]. In another study performed on subjects with fibrocalculated pancreatitis, PERT was associated with lower HbA1c and postprandial plasma glucose [25]. However, studies performed on small numbers of subjects with CP or T2D did not show any effect of PERT on post-prandial blood glucose, C-peptide secretion or on gastric emptying [26–28]. Conversely, PERT could also worsen glycemic control by increasing nutrients absorption. In one study performed on 18 subjects with CP and diabetes, one subject had major difficulties to attain acceptable glycemic control and one developed ketoacidosis after PERT initiation,

while two subjects experienced severe hypoglycemia after ceasing PERT [29]. However, these complications were not confirmed in other studies [10, 26]. A randomized, versus placebo study in subjects with insulin-treated diabetes mellitus and EPI showed that PERT could be used safely, and reduced the frequency of mild and moderate hypoglycemia [30].

Therefore, we aimed to study the real-life effects of PERT initiation on glycemic control in subjects with diabetes and EPI from any cause. In this study, we compared subjects with EPI and diabetes who were prescribed PERT with subjects with diabetes who had a relatively low fecal elastase-1 concentration (FEC) dosage, but did not receive PERT. The primary outcome was the effect of PERT on hypoglycemia frequency and severity. The secondary outcomes were the effects of PERT on gastro-intestinal disorders, HbA1c, body mass index (BMI), and on overall diabetes management.

## Methods

### Subjects

We conducted a retrospective study comparing participants with diabetes with or without PERT initiation. It was conducted at a tertiary referral center (the Diabetology Department of Cochin Hospital, Paris).

All subjects followed in our Diabetology Department who had PERT initiation between September 2013 and September 2022, and who were diagnosed with diabetes at least 3 months before PERT initiation, and who had severe EPI as defined by a FEC < 100 µg/g of stool, and who had at least one consultation in the department within the 2 years following PERT initiation were included in the PERT group. Subjects were defined as having PERT initiation if they received a prescription of pancreatin gastro-resistant capsules for the first time. In France, pancreatin is sold under 2 brand names: CREON® (Viatris Santé, France) or EUROBIOL® (Mayoly Spindler, France).

For the control group, we selected subjects followed in our Diabetology Department who did not receive PERT, matched on age and gender with the subjects from the PERT group (1:1). We selected subjects in whom a FEC dosage was performed between January 2016 and September 2022 with a relatively low result (<300 µg/g), in order to get clinically similar subjects to the PERT group. To be included, they also had to be diagnosed with diabetes at least 3 months before FEC dosage and to have at least one consultation in the department within the 2 years following FEC dosage.

### Materials and methods

We extracted all biological, radiological and clinical data from the subjects’ electronic medical records.
$T_0$ (index date) was defined as the date of initiation of PERT for the subjects from the PERT group, and as the date of FEC dosage for the subjects from the control group.

### Hypoglycemia

Frequent hypoglycemia was defined as the occurrence of at least 4 episodes of documented symptomatic hypoglycemia per week. Severe hypoglycemia was defined as hypoglycemia requiring the assistance of another person to administer glucose or sugar. Subjects were classified as having recent severe hypoglycemia if they experienced at least one episode of severe hypoglycemia within the last 2 years before $T_0$. Subjects were classified as having “relevant hypoglycemia” if they experienced frequent documented symptomatic hypoglycemia and/or experienced recent severe hypoglycemia. Improvement of hypoglycemia was deemed present if, during their follow-up visits (between 3 months and 2 years after $T_0$), the subjects reported that the frequency of relevant hypoglycemia decreased.

### Gastro-intestinal disorders

Subjects were classified as having gastro-intestinal disorders if they reported experiencing diarrhea, steatorrhea, nausea, or abdominal pain at least once a week. Improvement of gastro-intestinal disorders was deemed present if, during their follow-up visits (between 3 months and 2 years after $T_0$), subjects reported that the frequency of their usual digestive symptoms decreased.

### Recommended dosage of PERT

The European guidelines for the therapy of chronic CP recommend treating subjects with CP and EPI with enzyme replacement therapy (pancrelipase/pancreatin) of 40,000–80,000 units of lipase during main meals and half dose during snack meals [31, 32]. Subjects from the PERT group were classified into the recommended dosage (RD) subgroup if they were prescribed the appropriate dosage and in the underdosage (UD) subgroup if they were prescribed lower dosages.

### HbA₁c

To study the effect of PERT on HbA₁c, we defined baseline HbA₁c as the mean HbA₁c of each subject over the year prior to $T_0$, and follow-up HbA₁c as the mean HbA₁c over the year following $T_0$. Intra-subject variability was defined as follows: intra-subject variability of HbA₁c = follow-up HbA₁c of subject – baseline HbA₁c of said subject.

### Body mass index

To study the effect of PERT on BMI, we defined baseline BMI as the mean BMI of each subject over the 2 years

prior to $T_0$, and the follow-up BMI as the mean BMI over the 2 years following $T_0$. Intra-subject variability was defined as follows: intra-subject variability of BMI = follow-up BMI of subject – baseline BMI of said subject.

### Dosages

Vitamin A deficiency was defined as a vitamin A serum dosage < 1.5 µmol/L. Vitamin E deficiency was defined as a vitamin E serum dosage < 21 µmol/L.

### Statistical analysis

Statistics were performed using Graphpad Prism 9 (GraphPad Software, LLC).

Data are presented as mean and standard deviation (SD) for normally distributed variables, and as median and interquartile range (IQR) for variables with a non-normal distribution. For continuous variables, when the PERT and control groups were compared, we used unpaired t-test for normally distributed variables and Mann-Whitney test for variables with a non-normal distribution. When we studied intra-subject variability before and after $T_0$, we used paired t-test for normally distributed variables and Wilcoxon test for variables with a non-normal distribution. For categorical variables, we used Fisher's exact test when we compared 2 groups and Chi-square when we compared more than 2 groups. A p-value < 0.05 was considered statistically significant.

When data was missing, we reported the number of analysable participants in the corresponding table or figure.

Among the PERT group, we performed a subgroup analysis to compare subjects who were prescribed the recommended dosage of PERT with the ones who were not (RD and UD subgroups).

### Results

Forty-eight subjects were included in each group, 73% of the subjects were men (Table 1). Subjects treated with PERT presented more often with pancreatogenic diabetes than control subjects, who presented more often with T1D or T2D. Subjects treated with PERT had a lower BMI than control subjects. About 75% of subjects were treated with insulin in both groups. FEC was lower, and gastro-intestinal disorders, pancreas anomalies on CT, and vitamin A deficiency were more frequent in subjects treated with PERT than in control subjects. However, rates of relevant hypoglycemia were similar between groups.

### Comparison between subjects with and without PERT

#### Relevant hypoglycemia

In both groups, 15 subjects (31%: 4 subjects with T1D, 1 with T2D, 5 with pancreatogenic diabetes, 1 with
$T_0$ (index date) was defined as the date of initiation of PERT for the subjects from the PERT group, and as the date of FEC dosage for the subjects from the control group.

### Hypoglycemia

Frequent hypoglycemia was defined as the occurrence of at least 4 episodes of documented symptomatic hypoglycemia per week. Severe hypoglycemia was defined as hypoglycemia requiring the assistance of another person to administer glucose or sugar. Subjects were classified as having recent severe hypoglycemia if they experienced at least one episode of severe hypoglycemia within the last 2 years before $T_0$. Subjects were classified as having “relevant hypoglycemia” if they experienced frequent documented symptomatic hypoglycemia and/or experienced recent severe hypoglycemia. Improvement of hypoglycemia was deemed present if, during their follow-up visits (between 3 months and 2 years after $T_0$), the subjects reported that the frequency of relevant hypoglycemia decreased.

### Gastro-intestinal disorders

Subjects were classified as having gastro-intestinal disorders if they reported experiencing diarrhea, steatorrhea, nausea, or abdominal pain at least once a week. Improvement of gastro-intestinal disorders was deemed present if, during their follow-up visits (between 3 months and 2 years after $T_0$), subjects reported that the frequency of their usual digestive symptoms decreased.

### Recommended dosage of PERT

The European guidelines for the therapy of chronic CP recommend treating subjects with CP and EPI with enzyme replacement therapy (pancrelipase/pancreatin) of 40,000–80,000 units of lipase during main meals and half dose during snack meals [31, 32]. Subjects from the PERT group were classified into the recommended dosage (RD) subgroup if they were prescribed the appropriate dosage and in the underdosage (UD) subgroup if they were prescribed lower dosages.

### HbA₁c

To study the effect of PERT on HbA₁c, we defined baseline HbA₁c as the mean HbA₁c of each subject over the year prior to $T_0$, and follow-up HbA₁c as the mean HbA₁c over the year following $T_0$. Intra-subject variability was defined as follows: intra-subject variability of HbA₁c = follow-up HbA₁c of subject – baseline HbA₁c of said subject.

### Body mass index

To study the effect of PERT on BMI, we defined baseline BMI as the mean BMI of each subject over the 2 years

prior to $T_0$, and the follow-up BMI as the mean BMI over the 2 years following $T_0$. Intra-subject variability was defined as follows: intra-subject variability of BMI = follow-up BMI of subject – baseline BMI of said subject.

### Dosages

Vitamin A deficiency was defined as a vitamin A serum dosage < 1.5 µmol/L. Vitamin E deficiency was defined as a vitamin E serum dosage < 21 µmol/L.

### Statistical analysis

Statistics were performed using Graphpad Prism 9 (GraphPad Software, LLC).

Data are presented as mean and standard deviation (SD) for normally distributed variables, and as median and interquartile range (IQR) for variables with a non-normal distribution. For continuous variables, when the PERT and control groups were compared, we used unpaired t-test for normally distributed variables and Mann-Whitney test for variables with a non-normal distribution. When we studied intra-subject variability before and after $T_0$, we used paired t-test for normally distributed variables and Wilcoxon test for variables with a non-normal distribution. For categorical variables, we used Fisher's exact test when we compared 2 groups and Chi-square when we compared more than 2 groups. A p-value < 0.05 was considered statistically significant.

When data was missing, we reported the number of analysable participants in the corresponding table or figure.

Among the PERT group, we performed a subgroup analysis to compare subjects who were prescribed the recommended dosage of PERT with the ones who were not (RD and UD subgroups).

### Results

Forty-eight subjects were included in each group, 73% of the subjects were men (Table 1). Subjects treated with PERT presented more often with pancreatogenic diabetes than control subjects, who presented more often with T1D or T2D. Subjects treated with PERT had a lower BMI than control subjects. About 75% of subjects were treated with insulin in both groups. FEC was lower, and gastro-intestinal disorders, pancreas anomalies on CT, and vitamin A deficiency were more frequent in subjects treated with PERT than in control subjects. However, rates of relevant hypoglycemia were similar between groups.

### Comparison between subjects with and without PERT

#### Relevant hypoglycemia

In both groups, 15 subjects (31%: 4 subjects with T1D, 1 with T2D, 5 with pancreatogenic diabetes, 1 with
<table><caption>**Table 1** Characteristics of the subjects</caption><thead><tr><th></th><th>Subjects treated with PERT (n = 48)</th><th>Control group (n = 48)</th><th>p</th></tr></thead><tbody><tr><td>Subjects' characteristics</td><td></td><td></td><td></td></tr><tr><td>Age: years (mean, SD)</td><td>57 (14,8)</td><td>56 (14,3)</td><td>0.97</td></tr><tr><td>Male: n (%)</td><td>35 (73)</td><td>35 (73)</td><td></td></tr><tr><td>Tobacco use</td><td></td><td></td><td>0.38</td></tr><tr><td>Never: n (%)</td><td>17 (35)</td><td>23 (48)</td><td></td></tr><tr><td>Active user: n (%)</td><td>16 (33)</td><td>15 (31)</td><td></td></tr><tr><td>Former user: n (%)</td><td>15 (31)</td><td>10 (21)</td><td></td></tr><tr><td>Alcohol consumption</td><td></td><td></td><td>0.89</td></tr><tr><td>Never: n (%)</td><td>21 (44)</td><td>23 (48)</td><td></td></tr><tr><td>Occasional drinking: n (%)</td><td>13 (27)</td><td>10 (21)</td><td></td></tr><tr><td>Regular alcohol use: n (%)</td><td>5 (10)</td><td>6 (13)</td><td></td></tr><tr><td>Excessive drinking, current or stopped: n (%)</td><td>9 (19)</td><td>8 (17)</td><td></td></tr><tr><td>BMI at T<sub>0</sub>: kg/m<sup>2</sup>(median, IQR)</td><td>22.6 (19.9–26.7)</td><td>27.6 (22.5–29.6)</td><td>0.0022</td></tr><tr><td>Loss of weight at T<sub>0</sub> as compared to maximum weight ever: kg (median, IQR)</td><td>9.5 (4–16.3)</td><td>8.5 (3–15)</td><td>0.63</td></tr><tr><td>Diabetes</td><td></td><td></td><td></td></tr><tr><td>Diabetes duration: years (median, IQR)</td><td>12.1 (4.1–27.2)</td><td>14.9 (7.2–29.1)</td><td>0.59</td></tr><tr><td>Diabetes type</td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>Type 1 diabetes: n (%)</td><td>9 (19)</td><td>18 (38)</td><td></td></tr><tr><td>Type 2 diabetes: n (%)</td><td>8 (17)</td><td>21 (44)</td><td></td></tr><tr><td>Pancreatogenic diabetes: n (%)</td><td>18 (37)</td><td>0</td><td></td></tr><tr><td>Undetermined: n (%)</td><td>9 (19)</td><td>8 (17)</td><td></td></tr><tr><td>Other types (post-transplantation, post-PLD1 treatment, MODY): n (%)</td><td>4 (8)</td><td>1 (2)</td><td></td></tr><tr><td>Diabetes treatment at T<sub>0</sub></td><td></td><td></td><td></td></tr><tr><td>Insulin: n (%)</td><td>37 (77)</td><td>36 (75)</td><td>&gt;0.99</td></tr><tr><td>Metformin: n (%)</td><td>14 (29)</td><td>21 (44)</td><td>0.2</td></tr><tr><td>Sulfonylurea or repaglinide: n (%)</td><td>13 (27)</td><td>13 (27)</td><td>&gt;0.99</td></tr><tr><td>GLP1 agonist: n (%)</td><td>2 (4)</td><td>7 (15)</td><td>0.16</td></tr><tr><td>DPP4 inhibitor: n (%)</td><td>7 (15)</td><td>4 (8)</td><td>0.5</td></tr><tr><td>HbA<sub>1c</sub> at T<sub>0</sub>: % (median IQR)</td><td>8.7 (6.9–9.9)</td><td>8.4 (7.4–9.6)</td><td>0.94</td></tr><tr><td>HbA1c at T<sub>0</sub>: mmol/mol (median, IQR)</td><td>72 (52–85)</td><td>68 (57–81)</td><td></td></tr><tr><td>Retinopathy: n (%)</td><td>28 (58)</td><td>27 (56)</td><td>0.99</td></tr><tr><td>Neuropathy: n (%)</td><td>25 (52)</td><td>22 (46)</td><td>0.68</td></tr><tr><td>Nephropathy: n (%)</td><td>17 (35)</td><td>21 (44)</td><td>0.53</td></tr><tr><td>Ischemic cardiopathy: n (%)</td><td>7 (15)</td><td>11 (23)</td><td>0.43</td></tr><tr><td>Fasting C-peptide: nmol/L (median, IQR)</td><td>0.19 (0.04–0.36)</td><td>0.12 (0–0.33)</td><td>0.32</td></tr><tr><td>Exocrine pancreas</td><td></td><td></td><td></td></tr><tr><td>Fecal elastase-1 concentration: µg/g (median, IQR)</td><td>26.5 (0–72)</td><td>129 (102–192.8)</td><td>&lt;0.0001</td></tr><tr><td>Anomalies on pancreas CT<sup>†</sup></td><td></td><td></td><td></td></tr><tr><td>Pancreas atrophy: n (%)</td><td>28 (65)</td><td>8 (23)</td><td>0.0002</td></tr><tr><td>Pancreas calcifications: n (%)</td><td>19 (43)</td><td>5 (14)</td><td>0.0068</td></tr><tr><td>Vitamin A deficiency: n (%)<sup>‡</sup></td><td>8 (24)</td><td>0</td><td>0.007</td></tr><tr><td>Vitamin E deficiency: n (%)<sup>§</sup></td><td>9 (28)</td><td>2 (7)</td><td>0.051</td></tr><tr><td>Exocrine pancreatic insufficiency associated symptoms</td><td></td><td></td><td></td></tr><tr><td>More than 4 episodes of documented symptomatic hypoglycemia per week: n (%)</td><td>14 (29)</td><td>12 (25)</td><td>0.8</td></tr><tr><td>Recent history of severe hypoglycemia: n (%)</td><td>13 (27)</td><td>8 (17)</td><td>0.33</td></tr><tr><td>Relevant hypoglycemia (more than 4 events per week and/or recent severe hypoglycemia): n (%)</td><td>15 (31)</td><td>15 (31)</td><td>1</td></tr><tr><td>Gastrointestinal disorders: n (%)</td><td>21 (44)</td><td>10 (21)</td><td>0.02</td></tr></tbody></table>

PERT: Pancreatic Enzyme Replacement Therapy; SD: standard deviation; BMI: body mass index; IQR: interquartile range; CT: computed tomography

† Available in 44 subjects with PERT and 35 control subjects; ‡ available in 33 subjects with PERT and 26 control subjects; § available in 32 subjects with PERT and 27 control subjects
<table><caption>**Table 1** Characteristics of the subjects</caption><thead><tr><th></th><th>Subjects treated with PERT (n = 48)</th><th>Control group (n = 48)</th><th>p</th></tr></thead><tbody><tr><td>Subjects' characteristics</td><td></td><td></td><td></td></tr><tr><td>Age: years (mean, SD)</td><td>57 (14,8)</td><td>56 (14,3)</td><td>0.97</td></tr><tr><td>Male: n (%)</td><td>35 (73)</td><td>35 (73)</td><td></td></tr><tr><td>Tobacco use</td><td></td><td></td><td>0.38</td></tr><tr><td>Never: n (%)</td><td>17 (35)</td><td>23 (48)</td><td></td></tr><tr><td>Active user: n (%)</td><td>16 (33)</td><td>15 (31)</td><td></td></tr><tr><td>Former user: n (%)</td><td>15 (31)</td><td>10 (21)</td><td></td></tr><tr><td>Alcohol consumption</td><td></td><td></td><td>0.89</td></tr><tr><td>Never: n (%)</td><td>21 (44)</td><td>23 (48)</td><td></td></tr><tr><td>Occasional drinking: n (%)</td><td>13 (27)</td><td>10 (21)</td><td></td></tr><tr><td>Regular alcohol use: n (%)</td><td>5 (10)</td><td>6 (13)</td><td></td></tr><tr><td>Excessive drinking, current or stopped: n (%)</td><td>9 (19)</td><td>8 (17)</td><td></td></tr><tr><td>BMI at T<sub>0</sub>: kg/m<sup>2</sup>(median, IQR)</td><td>22.6 (19.9–26.7)</td><td>27.6 (22.5–29.6)</td><td>0.0022</td></tr><tr><td>Loss of weight at T<sub>0</sub> as compared to maximum weight ever: kg (median, IQR)</td><td>9.5 (4–16.3)</td><td>8.5 (3–15)</td><td>0.63</td></tr><tr><td>Diabetes</td><td></td><td></td><td></td></tr><tr><td>Diabetes duration: years (median, IQR)</td><td>12.1 (4.1–27.2)</td><td>14.9 (7.2–29.1)</td><td>0.59</td></tr><tr><td>Diabetes type</td><td></td><td></td><td>&lt;0.0001</td></tr><tr><td>Type 1 diabetes: n (%)</td><td>9 (19)</td><td>18 (38)</td><td></td></tr><tr><td>Type 2 diabetes: n (%)</td><td>8 (17)</td><td>21 (44)</td><td></td></tr><tr><td>Pancreatogenic diabetes: n (%)</td><td>18 (37)</td><td>0</td><td></td></tr><tr><td>Undetermined: n (%)</td><td>9 (19)</td><td>8 (17)</td><td></td></tr><tr><td>Other types (post-transplantation, post-PLD1 treatment, MODY): n (%)</td><td>4 (8)</td><td>1 (2)</td><td></td></tr><tr><td>Diabetes treatment at T<sub>0</sub></td><td></td><td></td><td></td></tr><tr><td>Insulin: n (%)</td><td>37 (77)</td><td>36 (75)</td><td>&gt;0.99</td></tr><tr><td>Metformin: n (%)</td><td>14 (29)</td><td>21 (44)</td><td>0.2</td></tr><tr><td>Sulfonylurea or repaglinide: n (%)</td><td>13 (27)</td><td>13 (27)</td><td>&gt;0.99</td></tr><tr><td>GLP1 agonist: n (%)</td><td>2 (4)</td><td>7 (15)</td><td>0.16</td></tr><tr><td>DPP4 inhibitor: n (%)</td><td>7 (15)</td><td>4 (8)</td><td>0.5</td></tr><tr><td>HbA<sub>1c</sub> at T<sub>0</sub>: % (median IQR)</td><td>8.7 (6.9–9.9)</td><td>8.4 (7.4–9.6)</td><td>0.94</td></tr><tr><td>HbA1c at T<sub>0</sub>: mmol/mol (median, IQR)</td><td>72 (52–85)</td><td>68 (57–81)</td><td></td></tr><tr><td>Retinopathy: n (%)</td><td>28 (58)</td><td>27 (56)</td><td>0.99</td></tr><tr><td>Neuropathy: n (%)</td><td>25 (52)</td><td>22 (46)</td><td>0.68</td></tr><tr><td>Nephropathy: n (%)</td><td>17 (35)</td><td>21 (44)</td><td>0.53</td></tr><tr><td>Ischemic cardiopathy: n (%)</td><td>7 (15)</td><td>11 (23)</td><td>0.43</td></tr><tr><td>Fasting C-peptide: nmol/L (median, IQR)</td><td>0.19 (0.04–0.36)</td><td>0.12 (0–0.33)</td><td>0.32</td></tr><tr><td>Exocrine pancreas</td><td></td><td></td><td></td></tr><tr><td>Fecal elastase-1 concentration: µg/g (median, IQR)</td><td>26.5 (0–72)</td><td>129 (102–192.8)</td><td>&lt;0.0001</td></tr><tr><td>Anomalies on pancreas CT<sup>†</sup></td><td></td><td></td><td></td></tr><tr><td>Pancreas atrophy: n (%)</td><td>28 (65)</td><td>8 (23)</td><td>0.0002</td></tr><tr><td>Pancreas calcifications: n (%)</td><td>19 (43)</td><td>5 (14)</td><td>0.0068</td></tr><tr><td>Vitamin A deficiency: n (%)<sup>‡</sup></td><td>8 (24)</td><td>0</td><td>0.007</td></tr><tr><td>Vitamin E deficiency: n (%)<sup>§</sup></td><td>9 (28)</td><td>2 (7)</td><td>0.051</td></tr><tr><td>Exocrine pancreatic insufficiency associated symptoms</td><td></td><td></td><td></td></tr><tr><td>More than 4 episodes of documented symptomatic hypoglycemia per week: n (%)</td><td>14 (29)</td><td>12 (25)</td><td>0.8</td></tr><tr><td>Recent history of severe hypoglycemia: n (%)</td><td>13 (27)</td><td>8 (17)</td><td>0.33</td></tr><tr><td>Relevant hypoglycemia (more than 4 events per week and/or recent severe hypoglycemia): n (%)</td><td>15 (31)</td><td>15 (31)</td><td>1</td></tr><tr><td>Gastrointestinal disorders: n (%)</td><td>21 (44)</td><td>10 (21)</td><td>0.02</td></tr></tbody></table>

PERT: Pancreatic Enzyme Replacement Therapy; SD: standard deviation; BMI: body mass index; IQR: interquartile range; CT: computed tomography

† Available in 44 subjects with PERT and 35 control subjects; ‡ available in 33 subjects with PERT and 26 control subjects; § available in 32 subjects with PERT and 27 control subjects
MODY-HNF1B and 4 undetermined in the PERT group; 10 subjects with T1D, 2 with T2D, 1 with post-transplantation diabetes and 2 undetermined in the control group) presented with relevant hypoglycemia. In both groups, relevant hypoglycemia was only noted in subjects treated with insulin, even though sulfonylureas were often prescribed in subjects with oral diabetes medication only. 41% of the subjects treated with PERT and insulin and 42% of the control subjects treated with insulin had relevant hypoglycemia. Hypoglycemia symptoms improved in 8 subjects after initiation of PERT, but also in 7 control subjects during the follow-up period (Fig. 1a). Of note, hypoglycemia symptoms improved in 4 out of the 5 subjects with pancreatogenic diabetes after PERT initiation (80%), versus in only 40% of subjects with other types of diabetes (NS).

### Gastro-intestinal disorders

44% of the subjects treated with PERT (6 subjects with T1D, 6 with pancreatogenic diabetes, one with MODY-HNF1B, one with post-PDL1 treatment diabetes and 9 undetermined) and 21% of the control subjects (5 subjects with T1D, 3 with T2D, one with post-transplantation diabetes and 1 undetermined) presented with gastro-intestinal disorders. These symptoms improved in 80% of subjects after initiation of PERT, versus in 20% of control subjects during the follow-up period (p = 0.002) (Fig. 1b). Gastro-intestinal disorders improved in all patients with T1D and pancreatogenic diabetes treated with PERT, and did not improve in 4 out of the 9 subjects with undetermined type of diabetes. In the control group, gastro-intestinal disorders improved in one subject with T2D and in one with post-transplantation diabetes.

### HbA1c

HbA1c decreased after the index date in both groups (Fig. 2a). Mean HbA1c decreased from 8.8 to 7.6% (73 to 60 mmol/mol) in the PERT group and from 8.2 to 7.6% (66 to 60 mmol/mol) in the control group (p = 0.0029 and p = 0.0038, respectively) (Fig. 2b). However, the intra-subject variability of HbA1c was only of – 0.5% in the PERT group and of – 0.28% in the control group, and the difference between the groups was not significant (Fig. 2c).

### BMI

BMI was stable over the study period in both groups (Fig. 3a). Notably, it did not increase after PERT initiation in the PERT group (Fig. 3b and c). In subjects with CP, BMI tended to increase after PERT initiation, from 24.9 to 25.8 kg/m², but the difference was not significant probably due to a lack of power.

### Hyperglycemia after PERT initiation

In the PERT group, 9 subjects (19%: 2 subjects with T1D, 3 with pancreatogenic diabetes, 2 with MODY HNF-1B and one undetermined) had notable hyperglycemia in the months after PERT initiation. Among them, one reported only partial compliance to his diabetes medication. Six subjects had to increase their insulin dosage by a few units to improve glycemic control. One subject with MODY HNF-1B was prescribed repaglinide, which improved glycemic control. Another subject with MODY HNF-1B had to be initiated on insulin in a context of infection and acute renal failure, and could reverse back to oral medication afterwards. There was no report of ketoacidosis or hospitalization for hyperglycemia.

Evolution of relevant hypoglycemia

<figure><img src="image_4.png" /><figcaption>**Fig. 1** Evolution of relevant hypoglycemia and of gastro-intestinal disorders over the study period. Black: PERT group White: Control group.</figcaption></figure>

a Evolution of relevant hypoglycemia in subjects treated with PERT and in control subjects, before and after T₀. Relevant hypoglycemia: at least 4 documented symptomatic hypoglycemia events per week and/or at least one episode of severe hypoglycemia within the last 2 years before T₀.

b Evolution of gastro-intestinal disorders before and after T₀ in subjects treated with PERT and in control subjects

Evolution of gastro-intestinal disorders

<figure><img src="image_5.png" /></figure>
MODY-HNF1B and 4 undetermined in the PERT group; 10 subjects with T1D, 2 with T2D, 1 with post-transplantation diabetes and 2 undetermined in the control group) presented with relevant hypoglycemia. In both groups, relevant hypoglycemia was only noted in subjects treated with insulin, even though sulfonylureas were often prescribed in subjects with oral diabetes medication only. 41% of the subjects treated with PERT and insulin and 42% of the control subjects treated with insulin had relevant hypoglycemia. Hypoglycemia symptoms improved in 8 subjects after initiation of PERT, but also in 7 control subjects during the follow-up period (Fig. 1a). Of note, hypoglycemia symptoms improved in 4 out of the 5 subjects with pancreatogenic diabetes after PERT initiation (80%), versus in only 40% of subjects with other types of diabetes (NS).

### Gastro-intestinal disorders

44% of the subjects treated with PERT (6 subjects with T1D, 6 with pancreatogenic diabetes, one with MODY-HNF1B, one with post-PDL1 treatment diabetes and 9 undetermined) and 21% of the control subjects (5 subjects with T1D, 3 with T2D, one with post-transplantation diabetes and 1 undetermined) presented with gastro-intestinal disorders. These symptoms improved in 80% of subjects after initiation of PERT, versus in 20% of control subjects during the follow-up period (p = 0.002) (Fig. 1b). Gastro-intestinal disorders improved in all patients with T1D and pancreatogenic diabetes treated with PERT, and did not improve in 4 out of the 9 subjects with undetermined type of diabetes. In the control group, gastro-intestinal disorders improved in one subject with T2D and in one with post-transplantation diabetes.

### HbA1c

HbA1c decreased after the index date in both groups (Fig. 2a). Mean HbA1c decreased from 8.8 to 7.6% (73 to 60 mmol/mol) in the PERT group and from 8.2 to 7.6% (66 to 60 mmol/mol) in the control group (p = 0.0029 and p = 0.0038, respectively) (Fig. 2b). However, the intra-subject variability of HbA1c was only of – 0.5% in the PERT group and of – 0.28% in the control group, and the difference between the groups was not significant (Fig. 2c).

### BMI

BMI was stable over the study period in both groups (Fig. 3a). Notably, it did not increase after PERT initiation in the PERT group (Fig. 3b and c). In subjects with CP, BMI tended to increase after PERT initiation, from 24.9 to 25.8 kg/m², but the difference was not significant probably due to a lack of power.

### Hyperglycemia after PERT initiation

In the PERT group, 9 subjects (19%: 2 subjects with T1D, 3 with pancreatogenic diabetes, 2 with MODY HNF-1B and one undetermined) had notable hyperglycemia in the months after PERT initiation. Among them, one reported only partial compliance to his diabetes medication. Six subjects had to increase their insulin dosage by a few units to improve glycemic control. One subject with MODY HNF-1B was prescribed repaglinide, which improved glycemic control. Another subject with MODY HNF-1B had to be initiated on insulin in a context of infection and acute renal failure, and could reverse back to oral medication afterwards. There was no report of ketoacidosis or hospitalization for hyperglycemia.

Evolution of relevant hypoglycemia

<figure><img src="image_3.png" /><figcaption>**Fig. 1** Evolution of relevant hypoglycemia and of gastro-intestinal disorders over the study period. Black: PERT group White: Control group.</figcaption></figure>

a Evolution of relevant hypoglycemia in subjects treated with PERT and in control subjects, before and after T₀. Relevant hypoglycemia: at least 4 documented symptomatic hypoglycemia events per week and/or at least one episode of severe hypoglycemia within the last 2 years before T₀.

b Evolution of gastro-intestinal disorders before and after T₀ in subjects treated with PERT and in control subjects

Evolution of gastro-intestinal disorders

<figure><img src="image_4.png" /></figure>
Evolution of HbA1c

<figure><img src="image_6.png" /></figure>

Mean HbA1c before and after T₀

Intra-subject variability of HbA1c

<figure><img src="image_7.png" /></figure>

<figure><img src="image_8.png" /></figure>

b

c

**Fig. 2** Evolution of HbA1c over the study period. a HbA1c (in %) at different time points before and after index date (T₀). Red circles: PERT group. Blue triangles: control group. b Mean HbA1c (in %) over the year prior and the year following T₀ in the PERT and control groups. Each dot or triangle represents a subject (n=46 in the PERT group, 40 in the control group). c Intra-subject variability of HbA1c in the PERT and control groups. Intra-subject variability of HbA1c = mean HbA1c of subject over the year following T₀ – mean HbA1c of said subject over the year prior to T₀. Each dot or triangle represents a subject (n=46 in the PERT group, 40 in the control group)

Adherence to PERT

Adherence to PERT can be rather difficult for subjects with EPI, because of the high number of capsules to take throughout the day. Three participants declared that they stopped taking PERT for several weeks or months, and 5 other participants had difficulty maintaining daily adherence to PERT. Among these 8 participants, 3 had gastrointestinal disorders, which improved in only one subject

after T₀. 1 had relevant hypoglycemia, which did not improve after T₀.

Comparison between subjects with recommended dosage and underdosage of PERT

In the PERT group, 14 subjects were not prescribed the recommended dosage. They were prescribed a mean of
Evolution of HbA1c

<figure><img src="image_5.png" /></figure>

<figure><img src="image_6.png" /><figcaption>**Fig. 2** Evolution of HbA1c over the study period. a HbA1c (in %) at different time points before and after index date (T₀). Red circles: PERT group. Blue triangles: control group. b Mean HbA1c (in %) over the year prior and the year following T₀ in the PERT and control groups. Each dot or triangle represents a subject (n=46 in the PERT group, 40 in the control group). c Intra-subject variability of HbA1c in the PERT and control groups. Intra-subject variability of HbA1c = mean HbA1c of subject over the year following T₀ – mean HbA1c of said subject over the year prior to T₀. Each dot or triangle represents a subject (n=46 in the PERT group, 40 in the control group)</figcaption></figure>

Adherence to PERT

Adherence to PERT can be rather difficult for subjects with EPI, because of the high number of capsules to take throughout the day. Three participants declared that they stopped taking PERT for several weeks or months, and 5 other participants had difficulty maintaining daily adherence to PERT. Among these 8 participants, 3 had gastrointestinal disorders, which improved in only one subject

after T₀. 1 had relevant hypoglycemia, which did not improve after T₀.

Comparison between subjects with recommended dosage and underdosage of PERT

In the PERT group, 14 subjects were not prescribed the recommended dosage. They were prescribed a mean of
<figure><img src="image_9.png" /><figcaption>**Fig. 3** Evolution of BMI over the study period. **a** BMI (in kg/m²) at different time points before and after index date (T₀). Red circles: PERT group. Blue triangles: control group. **b** Mean BMI (in kg/m²) over the 2 years prior and the 2 years following T₀ in the PERT and control groups. Each dot or triangle represents a subject (n=44 in the PERT group, 47 in the control group). **c** Intra-subject variability of BMI in the PERT and control groups. Intra-subject variability of BMI = mean BMI of subject over the 2 years following T₀ - mean BMI of said subject over the 2 years prior to T₀. Each dot or triangle represents a subject (n=44 in the PERT group, 47 in the control group)</figcaption></figure>

25,000 lipase units by meal. Thirty-four subjects were classified in the recommended dosage (RD) subgroup.

Relevant hypoglycemia symptoms improved in 55% (6 out of 11) of the RD subjects and 50% (2 out of 4) of the UD subjects (NS). Gastro-intestinal disorders improved in 87% (13 out of 15) of the RD subjects and 50% (2 out of 4) of the UD subjects (NS).

Mean HbA₁c decreased from 8.8 to 7.7% (73 to 61 mmol/mol) in the RD subgroup and from 8.9 to 7.6% (74 to 60 mmol/mol) in the UD subgroup (p=0.04 and 0.02,

respectively). Mean intra-subject variability of HbA₁c was of -0.4 and -0.9% in the RD and UD subgroups, respectively (NS). BMI was stable over the study period in both subgroups. Mean intra-subject variability of BMI was of -0.12 and +0.47 kg/m² in the RD and UD subgroups, respectively (NS).

Out of the 9 subjects who had notable hyperglycemia after PERT initiation, 3 subjects were in the UD subgroup.
<figure><img src="image_7.png" /><figcaption>**Fig. 3** Evolution of BMI over the study period. **a** BMI (in kg/m²) at different time points before and after index date (T₀). Red circles: PERT group. Blue triangles: control group. **b** Mean BMI (in kg/m²) over the 2 years prior and the 2 years following T₀ in the PERT and control groups. Each dot or triangle represents a subject (n=44 in the PERT group, 47 in the control group). **c** Intra-subject variability of BMI in the PERT and control groups. Intra-subject variability of BMI = mean BMI of subject over the 2 years following T₀ - mean BMI of said subject over the 2 years prior to T₀. Each dot or triangle represents a subject (n=44 in the PERT group, 47 in the control group)</figcaption></figure>

25,000 lipase units by meal. Thirty-four subjects were classified in the recommended dosage (RD) subgroup.

Relevant hypoglycemia symptoms improved in 55% (6 out of 11) of the RD subjects and 50% (2 out of 4) of the UD subjects (NS). Gastro-intestinal disorders improved in 87% (13 out of 15) of the RD subjects and 50% (2 out of 4) of the UD subjects (NS).

Mean HbA₁c decreased from 8.8 to 7.7% (73 to 61 mmol/mol) in the RD subgroup and from 8.9 to 7.6% (74 to 60 mmol/mol) in the UD subgroup (p=0.04 and 0.02,

respectively). Mean intra-subject variability of HbA₁c was of -0.4 and -0.9% in the RD and UD subgroups, respectively (NS). BMI was stable over the study period in both subgroups. Mean intra-subject variability of BMI was of -0.12 and +0.47 kg/m² in the RD and UD subgroups, respectively (NS).

Out of the 9 subjects who had notable hyperglycemia after PERT initiation, 3 subjects were in the UD subgroup.
Discussion

In this retrospective, monocentric study, we compared subjects with diabetes and EPI who were prescribed PERT for the first time, with control subjects who also presented with diabetes, had a FEC dosage and were not treated with PERT.

Frequent and or/severe hypoglycemia was a common
occurrence in both groups, and it was more common
in subjects treated with insulin. Over the study period,
hypoglycemia symptoms improved in about half of the
subjects, both in the PERT and the control groups. Thus,
we reckon that in this study, PERT was probably not the
main reason why hypoglycemia symptoms improved.
PERT initiation and FEC dosage were mainly performed
during hospitalization for educational purposes. The
decrease in hypoglycemia frequency and severity might
have resulted from improvement in diabetes manage-
ment and in subjects’ autonomy. The decrease in HbA1c
in both groups over the study period was probably due to
the same hospitalization effect. Our results are in accord-
ance with Ewald et al.’s study [30], which did not show any
difference in severe hypoglycemia rate after PERT initia-
tion either. It must however be noted that in the present
study relevant hypoglycemia symptoms improved in 80%
of subjects with pancreatogenic diabetes. PERT might
thus have a direct effect on hypoglycemia rate in subjects
with pancreatogenic diabetes, but there were too few
subjects to conclude definitively.

Conversely, the risk of severe hyperglycemia is often
mentioned when PERT initiation is considered in sub-
jects with diabetes [29]. We did not confirm this risk, as
we did not report any keto-acidosis or hospitalization
for hyperglycemia after PERT initiation. About one-fifth
of the subjects had minor hyperglycemia after PERT ini-
tiation. Among these subjects, about 80% percent had to
increase their insulin dosage by a few units, one subject
had to be initiated on insulin in a context of infection
and could reverse back to his usual treatment afterwards,
and one was started on repaglinide. In the control group,
one subject was initiated on insulin during the follow-up
period. Moreover, HbA1c globally decreased after PERT
initiation. Hence, as was previously shown [27, 30], PERT
initiation seems to be safe in subjects with diabetes. These
subjects should be advised to check their blood glucose
more closely in the weeks after PERT initiation in order to
adapt their treatment if needed. On a more general note,
side effects of PERT seem uncommon and mild in nature.
Mild nausea and headaches have mostly been reported
[9]. Aside from moderate hyperglycemia and occasional
constipation, the subjects treated with PERT in the pre-
sent study did not report any side effect of PERT.

Gastro-intestinal disorders were common in both
groups. This was expected, since FEC dosage is often

performed because of gastro-intestinal symptoms. Gas-
tro-intestinal disorders improved more often after PERT
initiation than in the control group. Gastro-intestinal
disorders also tended to improve more often in patients
with the recommended dosage of PERT than in patients
who were under-dosed, even though the difference was
non-significant, probably because of a lack of power in
this subgroup analysis. Thus, we reckon that PERT has
beneficial effects on gastro-intestinal disorders in sub-
jects with diabetes.

BMI was globally stable over the period of study. PERT initiation has previously been associated to an increase in weight, mostly in subjects with pancreatogenic diabetes [33]. Our study does not confirm this, but BMI should be interpreted with caution in our population: GLP1 treatment was initiated at T₀ in 5 subjects in the PERT group and 2 subjects in the control group. These subjects all lost or stabilized weight, as expected. Moreover, 3 subjects in the PERT group had pancreatic adenocarcinoma and lost weight progressively. Conversely, the BMI of subjects with CP and with T1D tended to increase after PERT initiation.

On another note, international guidelines recommend using 40,000–80,000 lipase units during main meals [31, 32]. These guidelines [34] were redacted for subjects with EPI and CP only, so there are no clear recommendations for subjects with more common types of diabetes and EPI. In the present study, a third of the subjects from the PERT group were not prescribed the recommended dosage. This is similar to what has been described elsewhere [35–37]. However, in the present study, HbA1c evolution, BMI evolution, and hypoglycemia’s improvement rate were similar in subjects with recommended dosage or under-dosage of PERT. The rate of moderate hyperglycemia after PERT initiation was also similar between subgroups. Improvement in gastro-intestinal disorders seemed to be more common in subjects with higher dosages of PERT than in subjects with under-dosage, but the difference was not significant. This concurs with what has been described in the literature: PERT effects on short and medium-term symptoms do not seem to correlate with PERT dosage, except for gastro-intestinal disorders [35]. Adapting PERT dosage with the aim of relieving gastro-intestinal symptoms seems a possible way to find the right amount of PERT per meal, in order to improve quality of life [14]. Yet, some subjects remain symptomatic even with high dosages, implying that other causes than EPI might be responsible for diarrhea or abdominal pain and should be sought for [36].

Our study bears some limitations. This was a retrospec-
tive study and data were obtained from electronical med-
ical records. Hence, the outcomes were only established
on what was reported and written down in the records.
Discussion

In this retrospective, monocentric study, we compared
subjects with diabetes and EPI who were prescribed
PERT for the first time, with control subjects who also
presented with diabetes, had a FEC dosage and were not
treated with PERT.

Frequent and or/severe hypoglycemia was a common
occurrence in both groups, and it was more common
in subjects treated with insulin. Over the study period,
hypoglycemia symptoms improved in about half of the
subjects, both in the PERT and the control groups. Thus,
we reckon that in this study, PERT was probably not the
main reason why hypoglycemia symptoms improved.
PERT initiation and FEC dosage were mainly performed
during hospitalization for educational purposes. The
decrease in hypoglycemia frequency and severity might
have resulted from improvement in diabetes manage-
ment and in subjects’ autonomy. The decrease in HbA1c
in both groups over the study period was probably due to
the same hospitalization effect. Our results are in accord-
ance with Ewald et al.’s study [30], which did not show any
difference in severe hypoglycemia rate after PERT initia-
tion either. It must however be noted that in the present
study relevant hypoglycemia symptoms improved in 80%
of subjects with pancreatogenic diabetes. PERT might
thus have a direct effect on hypoglycemia rate in subjects
with pancreatogenic diabetes, but there were too few
subjects to conclude definitively.

Conversely, the risk of severe hyperglycemia is often
mentioned when PERT initiation is considered in sub-
jects with diabetes [29]. We did not confirm this risk, as
we did not report any keto-acidosis or hospitalization
for hyperglycemia after PERT initiation. About one-fifth
of the subjects had minor hyperglycemia after PERT ini-
tiation. Among these subjects, about 80% percent had to
increase their insulin dosage by a few units, one subject
had to be initiated on insulin in a context of infection
and could reverse back to his usual treatment afterwards,
and one was started on repaglinide. In the control group,
one subject was initiated on insulin during the follow-up
period. Moreover, HbA1c globally decreased after PERT
initiation. Hence, as was previously shown [27, 30], PERT
initiation seems to be safe in subjects with diabetes. These
subjects should be advised to check their blood glucose
more closely in the weeks after PERT initiation in order to
adapt their treatment if needed. On a more general note,
side effects of PERT seem uncommon and mild in nature.
Mild nausea and headaches have mostly been reported
[9]. Aside from moderate hyperglycemia and occasional
constipation, the subjects treated with PERT in the pre-
sent study did not report any side effect of PERT.

Gastro-intestinal disorders were common in both
groups. This was expected, since FEC dosage is often

performed because of gastro-intestinal symptoms. Gas-
tro-intestinal disorders improved more often after PERT
initiation than in the control group. Gastro-intestinal
disorders also tended to improve more often in patients
with the recommended dosage of PERT than in patients
who were under-dosed, even though the difference was
non-significant, probably because of a lack of power in
this subgroup analysis. Thus, we reckon that PERT has
beneficial effects on gastro-intestinal disorders in sub-
jects with diabetes.

BMI was globally stable over the period of study. PERT initiation has previously been associated to an increase in weight, mostly in subjects with pancreatogenic diabetes [33]. Our study does not confirm this, but BMI should be interpreted with caution in our population: GLP1 treatment was initiated at T₀ in 5 subjects in the PERT group and 2 subjects in the control group. These subjects all lost or stabilized weight, as expected. Moreover, 3 subjects in the PERT group had pancreatic adenocarcinoma and lost weight progressively. Conversely, the BMI of subjects with CP and with T1D tended to increase after PERT initiation.

On another note, international guidelines recommend
using 40,000–80,000 lipase units during main meals [31,
32]. These guidelines [34] were redacted for subjects with
EPI and CP only, so there are no clear recommendations
for subjects with more common types of diabetes and
EPI. In the present study, a third of the subjects from the
PERT group were not prescribed the recommended dos-
age. This is similar to what has been described elsewhere
[35–37]. However, in the present study, HbA1c evolu-
tion, BMI evolution, and hypoglycemia’s improvement
rate were similar in subjects with recommended dosage
or under-dosage of PERT. The rate of moderate hyper-
glycemia after PERT initiation was also similar between
subgroups. Improvement in gastro-intestinal disorders
seemed to be more common in subjects with higher dos-
ages of PERT than in subjects with under-dosage, but the
difference was not significant. This concurs with what has
been described in the literature: PERT effects on short
and medium-term symptoms do not seem to correlate
with PERT dosage, except for gastro-intestinal disorders
[35]. Adapting PERT dosage with the aim of relieving
gastro-intestinal symptoms seems a possible way to find
the right amount of PERT per meal, in order to improve
quality of life [14]. Yet, some subjects remain sympto-
matic even with high dosages, implying that other causes
than EPI might be responsible for diarrhea or abdominal
pain and should be sought for [36].

Our study bears some limitations. This was a retrospec-
tive study and data were obtained from electronical med-
ical records. Hence, the outcomes were only established
on what was reported and written down in the records.
When data were missing, we mentioned it in the corresponding table or figure. Moreover, continuous glucose monitoring (CGM) has been widely available only since 2017 in France, and until very recently was only offered to subjects living with T1D. Therefore, CGM was available only in a small subset of the participants and CGM data was too scarce to be analyzed.

This was a real-life study, which on the one hand, allowed us to study subjects with different types of diabetes, with different types of diabetes medication, with varying dosages of and varying adherence to PERT. On the other hand, all these variables make the interpretation of results more difficult and less reproducible. Moreover, because of the design of the study, we were not able to find out if PERT has an effect on osteoporosis rate or survival in subjects with diabetes.

Another limitation is the definition of EPI itself: in our Diabetology Department, it is common to prescribe PERT in subjects with evocative symptoms and a FEC < 100 µg/g. In CP, EPI is usually defined by a FEC < 200 µg/g but the FEC threshold for EPI definition is still in debate [38]. Some authors even reckon that FEC is not reliable to define EPI in subjects with T1D [39], but others showed that a FEC < 100 µg/g correlated well with steatorrhea in subjects with T1D and T2D [40]. When in doubt (namely if the first stool sample was watery or if pancreas imaging was normal), FEC dosage should be reproduced to confirm the EPI diagnosis.

## Conclusions

In a retrospective, monocentric, real-life study, we compared 48 subjects with EPI and any type of diabetes who were prescribed PERT for the first time with 48 control subjects with diabetes who were not prescribed PERT. PERT prescription was associated with an improvement in gastro-intestinal disorders, but not in relevant hypoglycemia rate, with the possible exception of subjects with chronic pancreatitis. HbA1c and BMI evolution were similar between groups. PERT prescription was safe in subjects with diabetes, even though diabetes medication had to be mildly intensified in about one-fifth of the subjects after PERT initiation. PERT higher dosage tended to associate with stronger effects on gastro-intestinal disorders.

Hence, EPI should be sought for in subjects with diabetes and gastro-intestinal disorders, and PERT prescribed when appropriate. Prospective studies on PERT effects in subjects with diabetes would be useful to better understand its long-term effects in this population, and to confirm or infirm its beneficial effects on hypoglycemia rate and weight gain.

## Abbreviations

PERT Pancreatic enzyme replacement therapy

EPI Exocrine pancreatic insufficiency

## Acknowledgements

We would like to thank N. Kapel and L. Barbot-Trystram for the realization of FEC dosage.

## Author contributions

LAH conceived and designed the study, acquired data, analyzed and interpreted data, and drafted the manuscript. FY interpreted data and revised the manuscript critically. PBL interpreted data and revised the manuscript critically. DDL analyzed and interpreted data, and revised the manuscript critically. EL analyzed and interpreted data, and revised the manuscript critically. All authors have read and approved the final manuscript.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

## Declarations

### Ethics approval and consent to participate

This study was retrospective and used existing clinico-biological data only. According to the ethics regulation and French law, all the included subjects were informed of the study. The informed consent was waived according to French law due to the retrospective nature of the study. All the medical data were anonymized. The database was registered with the Commission Nationale Informatique et Libertés (CNIL) registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number AAA-2023-09047.

### Competing interests

The authors declare no competing interests.

### Author details

¹Service de Diabétologie, AP-HP, Hôpital Cochin, 123 boulevard de Port-Royal, 75014 Paris, France. ²Institut Cochin, INSERM, CNRS, Université Paris Cité, Paris, France. ³Sorbonne Université, INSERM, Nutrition and Obesities: Systemic approaches (NutriOmics), Paris, France. ⁴Service de Nutrition, AP-HP, Hôpital Pitié-Salpétrière, Paris, France.

Received: 8 December 2023 Accepted: 10 January 2024

Published online: 09 February 2024

## References

1. Das SLM, Kennedy JIC, Murphy R, Phillips ARJ, Windsor JA, Petrov MS. Relationship between the exocrine and endocrine pancreas after acute pancreatitis. World J Gastroenterol. 2014;20(45):17196-205.

2. Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev. 2012;28(4):338-42.

3. Foster TP, Bruggeman B, Campbell-Thompson M, Atkinson MA, Haller MJ, Schatz DA. Exocrine pancreas dysfunction in type 1 diabetes. Endocr Pract. 2020;26(12):1505-13.

4. Alexandre-Heymann L, Mallone R, Boitard C, Scharfmann R, Larger E. Structure and function of the exocrine pancreas in patients with type 1 diabetes. Rev Endocr Metab Disord. 2019. https://doi.org/10.1007/s11154-019-09501-3.

5. Zhang J, Hou J, Liu D, Lv Y, Zhang C, Su X, et al. The prevalence and characteristics of exocrine pancreatic insufficiency in patients with type 2 diabetes: a systematic review and meta-analysis. Int J Endocrinol. 2022;2022:7764963.
When data were missing, we mentioned it in the corresponding table or figure. Moreover, continuous glucose monitoring (CGM) has been widely available only since 2017 in France, and until very recently was only offered to subjects living with T1D. Therefore, CGM was available only in a small subset of the participants and CGM data was too scarce to be analyzed.

This was a real-life study, which on the one hand, allowed us to study subjects with different types of diabetes, with different types of diabetes medication, with varying dosages of and varying adherence to PERT. On the other hand, all these variables make the interpretation of results more difficult and less reproducible. Moreover, because of the design of the study, we were not able to find out if PERT has an effect on osteoporosis rate or survival in subjects with diabetes.

Another limitation is the definition of EPI itself: in our Diabetology Department, it is common to prescribe PERT in subjects with evocative symptoms and a FEC < 100 µg/g. In CP, EPI is usually defined by a FEC < 200 µg/g but the FEC threshold for EPI definition is still in debate [38]. Some authors even reckon that FEC is not reliable to define EPI in subjects with T1D [39], but others showed that a FEC < 100 µg/g correlated well with steatorrhea in subjects with T1D and T2D [40]. When in doubt (namely if the first stool sample was watery or if pancreas imaging was normal), FEC dosage should be reproduced to confirm the EPI diagnosis.

## Conclusions

In a retrospective, monocentric, real-life study, we compared 48 subjects with EPI and any type of diabetes who were prescribed PERT for the first time with 48 control subjects with diabetes who were not prescribed PERT. PERT prescription was associated with an improvement in gastro-intestinal disorders, but not in relevant hypoglycemia rate, with the possible exception of subjects with chronic pancreatitis. HbA1c and BMI evolution were similar between groups. PERT prescription was safe in subjects with diabetes, even though diabetes medication had to be mildly intensified in about one-fifth of the subjects after PERT initiation. PERT higher dosage tended to associate with stronger effects on gastro-intestinal disorders.

Hence, EPI should be sought for in subjects with diabetes and gastro-intestinal disorders, and PERT prescribed when appropriate. Prospective studies on PERT effects in subjects with diabetes would be useful to better understand its long-term effects in this population, and to confirm or infirm its beneficial effects on hypoglycemia rate and weight gain.

## Abbreviations

PERT Pancreatic enzyme replacement therapy

EPI Exocrine pancreatic insufficiency

## Acknowledgements

We would like to thank N. Kapel and L. Barbot-Trystram for the realization of FEC dosage.

## Author contributions

LAH conceived and designed the study, acquired data, analyzed and interpreted data, and drafted the manuscript. FY interpreted data and revised the manuscript critically. PBL interpreted data and revised the manuscript critically. DDL analyzed and interpreted data, and revised the manuscript critically. EL analyzed and interpreted data, and revised the manuscript critically. All authors have read and approved the final manuscript.

## Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

## Availability of data and materials

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

## Declarations

### Ethics approval and consent to participate

This study was retrospective and used existing clinico-biological data only. According to the ethics regulation and French law, all the included subjects were informed of the study. The informed consent was waived according to French law due to the retrospective nature of the study. All the medical data were anonymized. The database was registered with the Commission Nationale Informatique et Libertés (CNIL) registration number: 2203351v0. The study was approved by the local ethics committee CLEP, registration number AAA-2023-09047.

### Competing interests

The authors declare no competing interests.

### Author details

¹Service de Diabétologie, AP-HP, Hôpital Cochin, 123 boulevard de Port-Royal, 75014 Paris, France. ²Institut Cochin, INSERM, CNRS, Université Paris Cité, Paris, France. ³Sorbonne Université, INSERM, Nutrition and Obesities: Systemic approaches (NutriOmics), Paris, France. ⁴Service de Nutrition, AP-HP, Hôpital Pitié-Salpétrière, Paris, France.

Received: 8 December 2023 Accepted: 10 January 2024

Published online: 09 February 2024

## References

1. Das SLM, Kennedy JIC, Murphy R, Phillips ARJ, Windsor JA, Petrov MS. Relationship between the exocrine and endocrine pancreas after acute pancreatitis. World J Gastroenterol. 2014;20(45):17196-205.

2. Ewald N, Kaufmann C, Raspe A, Kloer HU, Bretzel RG, Hardt PD. Prevalence of diabetes mellitus secondary to pancreatic diseases (type 3c). Diabetes Metab Res Rev. 2012;28(4):338-42.

3. Foster TP, Bruggeman B, Campbell-Thompson M, Atkinson MA, Haller MJ, Schatz DA. Exocrine pancreas dysfunction in type 1 diabetes. Endocr Pract. 2020;26(12):1505-13.

4. Alexandre-Heymann L, Mallone R, Boitard C, Scharfmann R, Larger E. Structure and function of the exocrine pancreas in patients with type 1 diabetes. Rev Endocr Metab Disord. 2019. https://doi.org/10.1007/s11154-019-09501-3.

5. Zhang J, Hou J, Liu D, Lv Y, Zhang C, Su X, et al. The prevalence and characteristics of exocrine pancreatic insufficiency in patients with type 2 diabetes: a systematic review and meta-analysis. Int J Endocrinol. 2022;2022:7764963.
6. Clissold RL, Fulford J, Hudson M, Shields BM, McDonald TJ, Ellard S, et al. Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic. Clin Kidney J. 2018;11(4):453–8.

7. Alexandre-Heymann L, Lemoine AY, Nakib S, Kapel N, Ledoux S, Larger E. Nutritional markers in patients with diabetes and pancreatic exocrine failure. Acta Diabetol. 2019. https://doi.org/10.1007/s00592-019-01294-w.

8. de la Iglesia D, Vallejo-Senra N, López-López A, Iglesias-Garcia J, Lariño-Noia J, Nieto-García L, et al. Pancreatic exocrine insufficiency and cardiovascular risk in patients with chronic pancreatitis: a prospective, longitudinal cohort study. J Gastroenterol Hepatol. 2019;34(1):277–83.

9. Nakajima K, Oshida H, Muneyuki T, Kakei M. Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency. Core Evid. 2012;7:77–91.

10. Whitcomb DC, Bodhani A, Beckmann K, Sander-Struckmeier S, Liu S, Fuldeore M, et al. Efficacy and safety of pancrelipase/pancreatin in patients with exocrine pancreatic insufficiency and a medical history of diabetes mellitus. Pancreas. 2016;45(5):679–86.

11. Gubergrits N, Malecka-Panas E, Lehman GA, Vasileva G, Shen Y, Sander-Struckmeier S, et al. A 6-month, open-label clinical trial of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery. Aliment Pharmacol Ther. 2011;33(10):1152–61.

12. Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: a multi-center, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2):156–62.

13. Whitcomb DC, Lehman GA, Vasileva G, Malecka-Panas E, Gubergrits N, Shen Y, et al. Pancrelipase delayed-release capsules (CREON) for exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery: a double-blind randomized trial. Am J Gastroenterol. 2010;105(10):2276–86.

14. Czakó L, Takács T, Hegyi P, Prónai L, Tulassay Z, Lakner L, et al. Quality of life assessment after pancreatic enzyme replacement therapy in chronic pancreatitis. Can J Gastroenterol. 2003;17(10):597–603.

15. D'Haese JG, Ceyhan GO, Demir IE, Layer P, Uhl W, Löhr M, et al. Pancreatic enzyme replacement therapy in patients with exocrine pancreatic insufficiency due to chronic pancreatitis: a 1-year disease management study on symptom control and quality of life. Pancreas. 2014;43(6):834–41.

16. Vujasinovic M, Nezirevic Dobrijevic L, Asplund E, Rutkowski W, Dugic A, Kahn M, et al. Low bone mineral density and risk for osteoporotic fractures in patients with chronic pancreatitis. Nutrients. 2021;13(7): 2386.

17. Roberts KJ, Bannister CA, Schrem H. Enzyme replacement improves survival among patients with pancreatic cancer: results of a population based study. Pancreatology. 2019;19(1):114–21.

18. Domínguez-Muñoz JE, Nieto-García L, López-Díaz J, Lariño-Noia J, Abdulkader I, Iglesias-Garcia J. Impact of the treatment of pancreatic exocrine insufficiency on survival of patients with unresectable pancreatic cancer: a retrospective analysis. BMC Cancer. 2018;18(1):534.

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24. Perano SJ, Couper JJ, Horowitz M, Martin AJ, Kritas S, Sullivan T, et al. Pancreatic enzyme supplementation improves the incretin hormone response and attenuates postprandial glycemia in adolescents with cystic fibrosis: a randomized crossover trial. J Clin Endocrinol Metab. 2014;99(7):2486–93.

25. Mohan V, Poongothai S, Pitchumoni CS. Oral pancreatic enzyme therapy in the control of diabetes mellitus in tropical calculous pancreatitis. Int J Pancreatol. 1998;24(1):19–22.

26. Ebert R, Creutzfeldt W. Reversal of impaired GIP and insulin secretion in patients with pancreatogenic steatorrhea following enzyme substitution. Diabetologia. 1980;19(3):198–204.

27. Riceman MD, Bound M, Grivell J, Hatzinikolas S, Piotto S, Nguyen NQ, et al. The prevalence and impact of low faecal elastase-1 in community-based patients with type 2 diabetes. Diabetes Res Clin Pract. 2019;156:107822.

28. Glasbrenner B, Malfertheiner P, Kerner W, Scherbaum WA, Ditschuneit H. Effect of pancreatin on diabetes mellitus in chronic pancreatitis. Z Gastroenterol. 1990;28(6):275–9.

29. O'Keefe SJ, Cariem AK, Levy M. The exacerbation of pancreatic endocrine dysfunction by potent pancreatic exocrine supplements in patients with chronic pancreatitis. J Clin Gastroenterol. 2001;32(4):319–23.

30. Ewald N, Bretzel RG, Fantus IG, Hollenhorst M, Kloer HU, Hardt PD, et al. Pancreatin therapy in patients with insulin-treated diabetes mellitus and exocrine pancreatic insufficiency according to low fecal elastase 1 concentrations. Results of a prospective multi-centre trial. Diabetes Metab Res Rev. 2007;23(5):386–91.

31. Domínguez-Muñoz JE, Drewes AM, Lindkvist B, Ewald N, Czakó L, Rosendahl J, et al. Recommendations from the United European Gastroenterology evidence-based guidelines for the diagnosis and therapy of chronic pancreatitis. Pancreatology. 2018;18(8):847–54.

32. Phillips JA, Hopper AD, Leeds JS, Roberts KJ, McGeeney L, Duggan SN, et al. Consensus for the management of pancreatic exocrine insufficiency: UK practical guidelines. BMJ Open Gastroenterol. 2021;8(1): e000643.

33. Layer P, Kashirskaya N, Gubergrits N. Contribution of pancreatic enzyme replacement therapy to survival and quality of life in patients with pancreatic exocrine insufficiency. World J Gastroenterol. 2019;25(20):2430–41.

34. Shafiq N, Rana S, Bhasin D, Pandhi P, Srivastava P, Sehmby SS, et al. Pancreatic enzymes for chronic pancreatitis. Cochrane Database Syst Rev. 2009;4: CD006302.

35. Erchinger F, Tjora E, Nordaas IK, Dimcevski G, Olesen SS, Jensen N, et al. Pancreatic enzyme treatment in chronic pancreatitis: quality of management and adherence to guidelines-a cross-sectional observational study. United Eur Gastroenterol J. 2022;10(8):844–53.

36. Sikkens ECM, Cahen DL, van Eijck C, Kuipers EJ, Bruno MJ. Patients with exocrine insufficiency due to chronic pancreatitis are undertreated: a Dutch national survey. Pancreatology. 2012;12(1):71–3.

37. Barkin JA, Westermann A, Hoos W, Moravek C, Matrisian L, Wang H, et al. Frequency of appropriate use of pancreatic enzyme replacement therapy and symptomatic response in pancreatic cancer patients. Pancreas. 2019;48(6):780–6.

38. Vanga RR, Tansel A, Sidiq S, El-Serag HB, Othman MO. Diagnostic performance of measurement of fecal Elastase-1 in detection of exocrine pancreatic insufficiency: systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2018;16(8):1220-1228e4.

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40. Hardt PD, Hauenschild A, Nalop J, Marzeion AM, Jaeger C, Teichmann J, et al. High prevalence of exocrine pancreatic insufficiency in diabetes mellitus. A multicenter study screening fecal elastase 1 concentrations in 1,021 diabetic patients. Pancreatology. 2003;3(5):395–402.

## Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
6. Clissold RL, Fulford J, Hudson M, Shields BM, McDonald TJ, Ellard S, et al. Exocrine pancreatic dysfunction is common in hepatocyte nuclear factor 1β-associated renal disease and can be symptomatic. Clin Kidney J. 2018;11(4):453–8.

7. Alexandre-Heymann L, Lemoine AY, Nakib S, Kapel N, Ledoux S, Larger E. Nutritional markers in patients with diabetes and pancreatic exocrine failure. Acta Diabetol. 2019. https://doi.org/10.1007/s00592-019-01294-w.

8. de la Iglesia D, Vallejo-Senra N, López-López A, Iglesias-Garcia J, Lariño-Noia J, Nieto-García L, et al. Pancreatic exocrine insufficiency and cardiovascular risk in patients with chronic pancreatitis: a prospective, longitudinal cohort study. J Gastroenterol Hepatol. 2019;34(1):277–83.

9. Nakajima K, Oshida H, Muneyuki T, Kakei M. Pancrelipase: an evidence-based review of its use for treating pancreatic exocrine insufficiency. Core Evid. 2012;7:77–91.

10. Whitcomb DC, Bodhani A, Beckmann K, Sander-Struckmeier S, Liu S, Fuldeore M, et al. Efficacy and safety of pancrelipase/pancreatin in patients with exocrine pancreatic insufficiency and a medical history of diabetes mellitus. Pancreas. 2016;45(5):679–86.

11. Gubergrits N, Malecka-Panas E, Lehman GA, Vasileva G, Shen Y, Sander-Struckmeier S, et al. A 6-month, open-label clinical trial of pancrelipase delayed-release capsules (Creon) in patients with exocrine pancreatic insufficiency due to chronic pancreatitis or pancreatic surgery. Aliment Pharmacol Ther. 2011;33(10):1152–61.

12. Safdi M, Bekal PK, Martin S, Saeed ZA, Burton F, Toskes PP. The effects of oral pancreatic enzymes (Creon 10 capsule) on steatorrhea: a multi-center, placebo-controlled, parallel group trial in subjects with chronic pancreatitis. Pancreas. 2006;33(2):156–62.

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