Clinical Gastroenterology and Hepatology 2023;21:1214–1222

PANCREATOBILIARY
Association of Statin Usage and the Development of Diabetes
Mellitus after Acute Pancreatitis
Nikhil R. Thiruvengadam,1,2,3 Douglas E. Schaubel,4 Kimberly Forde,5 Peter Lee,6
Monica Saumoy,7 and Michael L. Kochman2,3
1
Division of Gastroenterology and Hepatology, Loma Linda University School of Medicine, Loma Linda, California;
2
Gastroenterology Division, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania; 3Center for
Endoscopic Innovation, Research and Training, Department of Medicine, Hospital of the University of Pennsylvania,
Philadelphia, Pennsylvania; 4Department of Biostatistics, Epidemiology, and Informatics, University of Pennsylvania,
Philadelphia, Pennsylvania; 5Department of Gastroenterology and Hepatology, Temple University, Philadelphia, Pennsylvania;
6
Department of Gastroenterology, Hepatology, and Nutrition, Ohio State University Wexner Medical Center, Columbus, Ohio;
and 7Center for Digestive Health, Penn Medicine Princeton Medical Center, Plainsboro, New Jersey

BACKGROUND: Patients with acute pancreatitis (AP) have at least a 2-fold higher risk for developing post-
pancreatitis diabetes mellitus (PPDM). No therapies have prevented PPDM. Statins were
demonstrated to possibly lower the incidence and severity of AP but have not been studied to
prevent PPDM.

METHODS: Data from a commercial insurance claim database (Optum Clinformatics) were used to assess
the impact of statins on patients without pre-existing DM admitted for a first episode of AP in
118,479 patients. Regular statin usage was defined as filled statin prescriptions for at least 80%
of the year prior to AP. The primary outcome was defined as PPDM. We constructed a pro-
pensity score and applied inverse probability of treatment weighting to balance baseline
characteristics between groups. Using Cox proportional hazards regression modeling, we
estimated the risk of PPDM, accounting for competing events.

RESULTS: With a median of 3.5 years of follow-up, the 5-year cumulative incidence of PPDM was 7.5%
(95% confidence interval [CI], 6.9% to 8.0%) among regular statin users and 12.7% (95% CI,
12.4% to 12.9%) among nonusers. Regular statin users had a 42% lower risk of developing
PPDM compared with nonusers (hazard ratio, 0.58; 95% CI, 0.52 to 0.65; P < .001). Irregular
statin users had a 15% lower risk of PPDM (hazard ratio, 0.85; 95% CI, 0.81 to 0.89; P < .001).
Similar benefits were seen with low, moderate, and high statin doses.

CONCLUSIONS: In a large database-based study, statin usage reduced the risk of developing DM after acute
pancreatitis. Further prospective studies with long-term follow-up are needed to study the
impact of statins on acute pancreatitis and prevention of PPDM.

Keywords: Statins; Postpancreatitis Diabetes Mellitus; Acute Pancreatitis; Late Complications of Pancreatitis.

ostpancreatitis diabetes mellitus (PPDM) is a
P subtype of diabetes mellitus (DM) that occurs as a
consequence of acute pancreatitis (AP) or chronic
pancreatitis.1 A systematic review of 1102 patients with
their first episode of AP found that up to 15% of patients
develop diabetes in the 12 months following their
episode of AP.2 Two subsequent nationwide studies in
Taiwan demonstrated that patients with AP had a 2-fold
higher risk of developing DM and that the risk was equiv-
alent in mild and severe AP.3,4 These studies suggest that
rather than the destruction of islet cells, other mecha-
nisms are responsible for PPDM. Potential mechanisms
for PPDM that have been studied include chronic low-
grade inflammation, lipolysis of fat cells, alteration of
the pancreas-gut-brain axis, and peripheral insulin
resistance.5–8
Statins are a class of medications that inhibit HMG-
CoA reductase in the cholesterol synthesis pathway and
have been shown to reduce cardiovascular mortality in
Abbreviations used in this paper: AHFS, American Hospital Formulary
Service; AP, acute pancreatitis; CI, confidence interval; DDD, defined daily
dose; DM, diabetes mellitus; HR, hazard ratio; ICD-10, International
Classification of Diseases–Tenth Revision; IPTW, inverse probability of
treatment weighting; PPDM, postpancreatitis diabetes mellitus.
Most current article
© 2023 by the AGA Institute
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https://doi.org/10.1016/j.cgh.2022.05.017

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1215
patients with coronary artery disease.9 Additionally,
statins have been shown to have pleiotropic effects,
including an anti-inflammatory effect, and have been
studied in various conditions with mixed results.10 While
there was an initial concern for drug-induced pancrea-
titis related to statins, recent epidemiologic studies have
shown that statins may reduce the risk of AP and
potentially limit its severity.11,12 Retrospective cohort
studies have also shown that statins may reduce the risk
of postendoscopic retrograde cholangiopancreatography
pancreatitis.13 While statins have been shown to have a
slightly increased risk of new-onset DM in susceptible
patients; they have not been studied in the prevention of
PPDM.14
We hypothesized that statin use initiated before a
patient’s first episode of AP is associated with reduced
rates of PPDM. To test this hypothesis, we used the
Optum Clinformatics database to compare PPDM among
patients who had used statins before their first episode
of AP and those who had never used statins.
Materials and Methods
Data Source
In this cohort study, we used administrative claims
data from Optum’s de-identifed Clinformatics Data Mart
Database, a data warehouse of adjudicated claims for
commercial and Medicare advantage covered individuals.
The Clinformatics database consists of medical and
pharmacy insurance claims, with data available for 71
million unique patients. The study used de-identified
data and was determined to be exempt from review by
the Institutional Review Board of the University of
Pennsylvania.
Study Population
Persons with AP diagnosed between January 1, 2008,
and January 1, 2021, were identified using the Interna-
tional Classification of Diseases (ICD)–Ninth Revision
code 577.0 (acute pancreatitis) and using the ICD–Tenth
Revision (ICD-10) code K85 (primary and secondary
codes for acute pancreatitis), which have been previously
validated.15,16 These diagnosis codes were confirmed by
the addition of a lipase greater than 3 times the upper
limit of normal (Supplementary Index 1). One year of
continuous enrollment in medical and prescription drug
services prior to the first episode of AP was required.
Statin Use
All statin usage was classified as the American Hos-
pital Formulary Service (AHFS) code 240608; we
excluded users of other cholesterol-lowering medica-
tions (defined as AHFS 240604, 240605, 240606, and
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What You Need to Know
Background
Patients who develop acute pancreatitis (AP) have a
2- to 3-fold higher risk for developing diabetes, with
up to 15% of patients developing diabetes in the first
2 years.
Findings
Regular statin usage was associated with a 42%
lower risk of developing diabetes in AP patients and
lower rates of insulin-dependent diabetes.
Implications for Patient Care
Statins may prevent postpancreatitis diabetes and
should be considered in patients with AP. Further
prospective studies are needed to examine the role
of statins in AP.
240624) (Supplementary Table 1) to isolate the effects of
statins.
The defined daily dose (DDD) per day for statin users
was estimated as the total defined daily dose (the total
milligrams dispensed divided by the average maintenance
dose of that statin as defined by the World Health Organi-
zation) divided by the time in days between the first statin
prescription and the last prescription before the onset of AP
(Supplementary Index 2).17 Statin doses were analyzed in
the following categories of DDD per day: 0.00 (reference),
0.01–0.75, 0.76–1.50, and more than 1.50. These DDD
categories were used because they have been defined by
the World Health Organization and have been demon-
strated to correlate with low, medium, and high potency.18
Patients who had statin prescriptions filled for at least
80% of the 1 year preceding their diagnosis of AP were
classified as regular statin users. In comparison, irregular
statin users were patients who had statin prescriptions
for <80% of the 1 year preceding their diagnosis of AP.
More than 80% usage of statins was chosen, as it has been
shown to correlate with long-term consistent use.19,20
Nonstatin users had no prescriptions for statins within
12 months before the onset of AP or any prescriptions
followed the onset of AP. To exclude reverse causation,
statin usage was measured only before the onset of AP,
and we did not include statin usage after the diagnosis of
AP (Supplementary Index 3). We excluded any statin
nonusers who started statins after the onset of AP and
prior to the development of PPDM.
We also considered whether patients had ever used
statins in an analysis in which all patients with AP who
had ever received a statin before their first episode of AP
were compared with those who had never used statins.
Outcomes
The primary outcome of this study was the develop-
ment of PPDM. Diabetes was defined as at least 1
1216 Thiruvengadam et al
physician claim with the diagnosis of diabetes in any of
the diagnosis fields (ICD–Ninth Revision code 250; ICD-
10 codes E10, E11, E13, E14, the primary and second-
ary codes for DM) and at least 1 prescription for an oral
or subcutaneous hypoglycemic medication or insulin
(AHFS codes 682002, 682003, 682004, 682005, 682006,
682008, 682016, 682020, 682028, and 682092). This
definition has previously been shown to maximize the
sensitivity and specificity for the diagnosis of diabetes in
administrative healthcare datasets (Supplementary
Index 4).21 Patients who had a pre-existing diagnosis of
diabetes before or on the day of their diagnosis of AP
were excluded.
Statistical Analysis
Primary Analysis. The start of follow-up for the
development of diabetes was the first day of the first
admission for AP. The end of follow-up was the devel-
opment of diabetes, death, loss to insurance follow-up, or
June 31, 2021 (end of available data), whichever
occurred first. Death and diabetes onset present
competing risks. We modeled the cause-specific hazard22
of diabetes incidence; this represents the rate of PPDM
onset among patients at risk (ie, alive and PPDM-free).
We chose to model the cause-specific hazards because
they are mechanistic in nature in contrast to the sub-
distribution hazard, which is descriptive (or consequen-
tial) in nature.22
Our implementation of Cox regression consisted of 2
stages. At the first stage, we applied inverse probability
of treatment weighting (IPTW) to balance the statin and
nonstatin using patient groups. Specifically, after IPTW,
the weighted version of the 2 groups has the same
adjustment covariate distributions. Technically, we could
then use Cox regression with only a regular statin indi-
cator (0 ¼ no; 1 ¼ yes). However, in the interest of
robustness, we included all adjustment covariates.
Adjustment covariates included demographic factors
(age, sex, race), medical comorbidities (Supplementary
Index 5), the severity of pancreatitis (Supplementary
Index 6 and 7), other medications, calendar year, and
laboratory tests. To evaluate the performance of
weighting, we compared the standardized mean differ-
ences between individual covariates between groups
before and after IPTW with a difference of 0.1 indicating
adequate balance of covariates (Supplementary Index 8
and 9).23
Schoenfeld residual tests identified no violations of
the proportional hazards assumption.24
Secondary Analyses. Cumulative incidence curves
were plotted utilizing the method as specified by Fine
and Gray.25 This was done for descriptive purposes.
We assessed whether the associations varied by
prespecified risk factors. We evaluated the relationship
between the nature of statin usage (regular use, irregular
use, and nonusage) and the defined daily dose of statin
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Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5
and the PPDM. We also looked at the impact of regular
statin usage on insulin-dependent PPDM (defined as
PPDM requiring insulin). Finally, we compared patients
who had ever received a statin prior to developing AP to
statin nonusers.
Sensitivity Analyses. We performed a variety of
sensitivity analyses including analyzes a propensity-
matched 1:1 sample, stratifying the results by develop-
ment of pancreatic adenocarcinoma and by severity of
pancreatitis and finally used both a negative control
outcome (low-energy fractures) and negative control
exposure (beta-blockers) to evaluate for unmeasured
confounding (see Supplementary Index 10). Finally, we
calculated the E-value to identify the minimum strength
of association that an unmeasured confounder would
need to have with both treatment and outcome, condi-
tional on the measured covariates, to explain away the
observed associations between statin usage and the
development of PPDM.26
All statistical analyses were performed with STATA
17 statistical package (StataCorp LP, College Station, TX).
A P value <.05 was considered statistically significant.
Results
Study Population
We included 118,479 patients who had a first hos-
pitalization from 2008 to 2020, and these patients were
followed for 385,109 patient-years of follow-up (median
3.5 [range, 0.5–12.8] years). A total of 66,000 patients
who used other cholesterol-lowering medications and
4496 statin nonusers who were exposed to statins after
the development of AP and prior to the development of
PPDM were excluded. Among the included patients,
82,159 (69.3%) did not use statins or any cholesterol-
lowering medication prior to their diagnosis of AP
(non–statin users), while 9048 (7.6%) used statins
regularly (regular statin users), and 27,272 (23.0%)
patients used statins for <80% of the 365 days prior to
their diagnosis of AP (irregular statin users) (Figure 1).
The baseline characteristics of the patients are shown in
Table 1. Among statin users, the median age was 73
years, 20% had ischemic heart disease, 90% had hy-
pertension, and 25% were obese. After adjustment for
the IPTW, all covariates were well balanced (ie, stan-
dardized mean differences were <0.1). Overall, 12,590
(10.10%) patients developed PPDM.
Regular Statin Use and PPDM
The 5-year cumulative incidence of PPDM was 7.5%
(95% confidence interval [CI], 6.9% to 8.0%) among
regular statin users and 12.65% (95% CI, 12.4% to
12.9%) among nonusers (a difference of 5.2%; 95%
CI, 7.4 to4.3; P < .001).
May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1217
Figure 1. Selection of AP patients
entering into the study divided into
regular statin use and no statin use.
Regular statin users had a 42% lower risk of
developing PPDM compared with nonusers, with a
hazard ratio (HR) of 0.58 (95% CI, 0.52 to 0.65; P <
.001), as depicted in Figure 2. The test for the pro-
portional hazards assumption with Schoenfeld re-
siduals gave a P value of .13, indicating that the
proportional hazards assumption was met. Patients
who had ever received a statin prior to AP were 13%
less likely to develop PPDM (HR, 0.87; 95% CI, 0.82 to
0.94; P < .001). When we excluded early pancreatitis
(within 3 months), regular statin users had a 34%
lower risk of developing diabetes after pancreatitis
compared with nonusers. (HR, 0.66; 95% CI: 0.57 to
0.76; P < .001).
Consistency of Statin Usage and PPDM
The risk of PPDM was also influenced by the consis-
tency of statin use. Compared with statin nonusers,
irregular statin users had a 15% lower risk of PPDM (HR,
0.85; 95% CI, 0.81 to 0.89; P < .001), while regular statin
users had a 42% lower risk of PPDM (HR, 0.58; 95% CI,
0.52 to 0.65; P < .001) (Figure 3).
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Statin Dose and PPDM
The multivariable-adjusted HRs for PPDM according
to the defined daily statin dose, as compared with no
statin use, were 0.45 (95% CI, 0.36 to 0.57; P < .001) for
a dose of 0.01–0.75 defined daily dose, 0.58 (95% CI,
0.49 to 0.70; P < .001) for 0.76–1.50 defined daily dose,
and 0.70 (95% CI, 0.56 to 0.89; P < .001) for higher than
1.50 defined daily dose. (Figure 4) A linear regression
model modeling the relationship between the defined
daily dose and PPDM did not demonstrate a linear dose-
response relationship (P ¼ .16)
Regular Statin Use and Insulin-Dependent
PPDMDM
The 5-year cumulative incidence of insulin-
dependent PPDM was 2.4% (95% CI 1.3% to 3.0%)
among regular statin users and 6.6% (95% CI, 6.2% to
6.9%) among nonusers. Regular statin users had a
52% lower risk of developing insulin-dependent DM
compared with nonusers (HR, 0.48; 95% CI, 0.41 to
0.56; P < .001).
1218 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Table 1. Baseline Characteristics of the Regular Statin Users and Non–Statin Users

Non–Statin Regular-Statin Standardized Mean Standardized Mean

Users (n ¼ 82,159) Users (n ¼ 9,048) Difference Before IPTW Difference After IPTW

Patient characteristics
Age, y 58 (42–73) 74 (66–81) 1.00 –0.05
Male 38,683 (47.1) 4494 (49.7) 0.06 0.01
Age-adjusted Charlson 3 (1–6) 5 (3–8) 0.47 –0.06
comorbidity index
Race –0.11 –0.04
White 51,477 (62.7) 6409 (70.8)
Black 8576 (10.4) 622 (6.9)
Hispanic 9668 (11.8) 834 (9.2)
Asian 1967 (2.4) 185 (2.0)
Unknown 10,471 (12.7) 998 (11.0)
Pancreatitis characteristics
Etiology of pancreatitis 0.05 –0.01
ETOH/gallstones 15,895 (19.3) 1779 (19.7)
ETOH 17,888 (21.8) 1277 (14.1)
Gallstones 29,325 (35.7) 3872 (42.8)
Post-ERCP 2462 (3.0) 320 (3.5)
Other 16,589 (20.2) 1800 (19.9)
Number of AP hospitalizations 1 (1–2) 1 (1–4) 0.03 –0.01
Length of stay, d 4 (3–7) 4 (3–7) 0.30 –0.006
Severity of pancreatitis
ICU admission 17,739 (21.6) 1690 (18.7) 0.09 0.009
SOF during index AP hospitalization 12,083 (14.8) 2144 (23.7) 0.13 0.004
MOF during index AP hospitalization 3040 (3.7) 454 (5.0) 0.07 0.009
OF by organ system
Pulmonary 4056 (4.9) 608 (6.7) 0.08 0.0007
Cardiac 1422 (1.7) 228 (2.5) 0.06 0.005
Renal 9466 (11.5) 1412 (15.6) 0.11 –0.003
Neurologic 1425 (1.7) 147 (1.6) 0.03 0.0007
Hematologic 1261 (1.5) 181 (2.0) –0.01 0.002
Hepatic 957 (1.2) 84 (0.9) –0.02 0.001
Metabolic 3388 (4.1) 363 (4.0) –0.007 –0.003
Require procedural intervention for AP 5930 (7.2) 721 (8.0) 0.03 –0.007
Nutritional support
Enteral nutrition 4034 (4.9) 482 (5.3) 0.03 –0.01
Parenteral nutrition 2939 (3.6) 284 (3.1) –0.03 –0.02
Medical comorbidities
Ischemic heart disease 5296 (6.4) 1848 (20.4) 0.42 –0.05
Hypertension 43,047 (52.4) 8119 (89.7) 0.93 –0.02
Obesity 15,916 (19.4) 2268 (25.1) 0.12 –0.004
Cerebrovascular disease 1952 (2.4) 515 (5.7) 0.15 –0.01
Pancreatic cancer 484 (0.6) 83 (0.9) 0.09 0.001

Values are median (interquartile range) or n (%).

AP, acute pancreatitis; ETOH, alcohol; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit; IPTW, inverse probability of treatment
weighting; MOF, multiple organ failure; OF, organ failure; SOF, single organ failure.

Sensitivity Analyses
Propensity-Matched Cohort (1:1). A total of 8171
regular statin users were matched to 8171 nonusers
(Supplementary Index 11). They were comparable in
their baseline characteristics (see Supplementary
Table 6 for baseline characteristics of the matched
cohort). Regular statin usage in the matched cohort
showed a similar risk reduction as the primary
analysis (HR, 0.61 ;95% CI, 0.54 to 0.68; P < .001)
(Figure 5).
Pancreatic Cancer. A total of 378 (4.3%) regular statin
users and 2315 (2.8%) nonusers developed pancreatic
cancer after AP. A similar benefit was seen with regular
statin usage in patients who did not develop pancreatic
cancer (HR, 0.54; 95% CI, 0.49 to 0.59; P < .001)
compared with patients who developed pancreatic can-
cer. (HR, 0.59; 95% CI, 0.31 to 0.85; P < .001).

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1219

Figure 2. Cumulative incidence of

PPDM among statin users and
nonusers.

Additional Sensitivity Analyses
Our results were consistent across all sensitivity an-
alyses, including those performed when we limited the
analysis to persons with more detailed data regarding
the severity of pancreatitis (patients for whom ICD-10
codes were used) Results were similar in patients who
presented in the ICD-10 era (HR, 0.40; 95% CI, 0.33 to
0.44; P < .001) and patients with necrotizing pancreatitis
only (HR, 0.54; 95% CI, 0.35 to 0.82; P < .001). When the
analysis was limited to patients with severe pancreatitis,
regular statin usage reduced the risk of PPDM by 60%
(HR, 0.40 95% CI, 0.34 to 0.44; P < .001). Similar results
were found in patients with mild pancreatitis (HR, 0.60;
95% CI, 0.53 to 0.67; P < .001, Supplementary Index 12).
Additional analyses were conducted, using both a
negative control exposure and a negative control
outcome, to detect whether the results of the primary
analysis were inherently biased or confounded.
(Supplementary Index 13 and 14) First, the association
between regular usage of beta-blockers and the devel-
opment of PPDM was evaluated using IPTW. There was

Figure 3. Cumulative incidence of

PPDM comparing the consistency of
statin usage.

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1220 Thiruvengadam et al
no association between regular beta-blocker usage and
PPDM (HR, 0.99; 95% CI, 0.91 to1.07; P ¼ .34). We next
evaluated the impact of regular statin usage on low-
energy fractures and found no impact of regular statin
usage (HR, 0.90; 95% CI, 0.79 to 1.02; P ¼ .14). When
limited to patients who had an annual preventative
outpatient visit in the year prior to AP, regular statin
usage had a similar impact on PPDM (HR, 0.69; 95% CI,
0.59 to 0.89; P ¼ .006, Supplementary Index 15).
Finally, the bias analyses showed that a putative
confounder would need to be very large to nullify the
negative association detected between regular statin
usage and diabetes; it would need to increase the risk of
PPDM by almost 3-fold and be 3 times more common
Figure 5. Cumulative incidence of
PPDM among statin users and non-
users after 1:1 propensity matching.
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Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5
Figure 4. Cumulative incidence of
PPDM comparing statin dose levels.
among nonusers than regular statin users (E-values:
overall ¼ 2.84) (Supplementary Index 16).
Discussion
In this cohort study of 118,479 patients with their
first episode of AP, the use of statins was associated with
a substantially lower risk of PPDM. The benefits of sta-
tins depended on the consistency of usage, with regular
users having a significantly lower risk of PPDM than
irregular users. Our results did not indicate a dose-
response relationship for statins and PPDM, suggesting
that high-dose statins may not be more effective in
May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1221
preventing PPDM compared with low-dose statins. The
benefits of statins were seen across sex, etiologies of
pancreatitis, and in both mild and severe AP, suggesting
that a broad population of AP patients may benefit from
statins.
It may seem paradoxical that statins could prevent
PPDM, as there is an epidemiologic association with a
slight increase in new-onset DM with statin initiation.
This finding was first reported in the Justification for
the Use of Statins in Primary Prevention: An Interven-
tion Trial Evaluating Rosuvastatin (JUPITER) trial, eval-
uating rosuvastatin to prevent coronary disease, which
reported a 27% increase in new-onset diabetes with
rosuvastatin.27 Subsequent meta-analyses have shown a
slightly increased risk (1.1 to 1.2-fold) of type 2 diabetes
following statin initiation, with the risk primarily being
in patients at high risk for diabetes (patients with pre-
diabetes, obesity, and metabolic syndrome).28 However,
studies have demonstrated that type 2 diabetes and
PPDM have very different clinical features and under-
lying pathophysiology. Studies comparing type 2 DM and
PPDM patients have shown that PPDM patients have
much higher rates of requiring insulin, hospitalization,
and all-cause mortality than patients with type 2 DM.29
Type 2 DM is driven by peripheral insulin resistance
as well as by adipose tissue releasing proinflammatory
cytokines, leading to beta-cell dysfunction, while PPDM
is thought to be driven by chronic low-grade inflam-
mation after AP that is driven by interleukin-6 and tu-
mor necrosis factor a, thereby leading to hyperglycemia
and diabetes.6,7 Statins have previously been shown to
reduce tumor necrosis factor a secretion in activated T
lymphocytes and have reduced the production of C-
reactive protein in response to circulating interleukin-6
in hepatocytes, and these mechanisms may explain
their protection against PPDM.30
No therapy has been previously studied for prevent-
ing any of the late complications of AP. Our study
demonstrated a significant reduction in PPDM rates with
statin therapy, and it has the following clinical implica-
tions. First, it highlights the importance of dedicated
posthospitalization follow-up to monitor for PPDM and
discuss potential ways to reduce this risk with AP pa-
tients. Second, our results suggest that the gastroenter-
ologists and primary care physicians who are seeing
outpatients discharged after hospitalization for AP
should consider the usage of statins, particularly in those
who may have another possible indication for statin
therapy, such as mild hyperlipidemia. These results
should also inform longitudinal prospective cohort
studies of AP, such as the Diabetes RElated to Acute
Pancreatitis and Its Mechanisms (DREAM) study
(https://clinicaltrials.gov/ct2/show/NCT05197920), to
examine statin usage and its relationship with PPDM and
inform randomized controlled trials of statins in AP to
examine long-term outcomes as well, mainly PPDM. Our
study is the first to demonstrate an association between
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a well-studied, inexpensive therapy, statins, and reduced
rates of PPDM. This can generate hypotheses for future
studies and provide another possible treatment for cli-
nicians to utilize as there are currently no proven ther-
apies to prevent PPDM.
Strengths of this study include the large population
size using a longitudinal dataset that contains 7% of the
U.S. population and has been found to be a representa-
tive sample of the general population.31 We applied
numerous analytic approaches to address potential bias,
including outcome validation (using laboratory data) and
multiple sensitivity analyses (including stratification for
the severity of pancreatitis) supporting our primary
findings. The attribution of the lower risk of PPDM due to
statin use was supported by negative control exposure,
and outcome analyses, which showed that there was no
difference in the risk of low-energy fractures between
the regular statin user and statin nonuser groups and
regular beta-blocker usage was not associated with
PPDM.
We acknowledge several limitations of our study.
First, we lacked information regarding radiologic find-
ings, inpatient treatments and specific severity grade of
pancreatitis, and screening for DM. Furthermore, owing
to the structure of the databases used in the study, we
know that the statins were prescribed and dispensed by
the pharmacy, but we do not know whether or how the
patients took them. Third, there could have been
treatment-related selection bias. We used multiple
methods to account for this, including combining multi-
variable Cox regression and IPTW and a propensity-
matched model with greedy matching.
Another limitation is the possibility that statin use
was a marker of increased health awareness, creating a
healthy-user bias. As expected, statin users were more
likely to have obesity, cardiovascular disease, and pre-
existing diabetes. However, even when we performed
1:1 propensity score matching, statin usage was associ-
ated with a significantly lower risk of postpancreatitis
DM. We also performed negative control exposure and
outcome analysis that showed no impact of statins on
low-energy fractures (a potential sign of less healthy
behaviors) and that another widely prescribed medica-
tion class, beta-blockers, did not have an impact on
PPDM. Finally, although residual unmeasured con-
founding is possible, our E-value sensitivity analysis in-
dicates that an unmeasured confounder would need to
be highly imbalanced between statin users and nonusers
and strongly associated with postpancreatitis to entirely
negate the effect of statins.
In conclusion, among patients with AP, we observed
an association between statin use at the time of pre-
sentation and a reduced risk of PPDM, with a reduction
of up to 42%. Our findings support the need for ran-
domized clinical trials with longitudinal follow-up
designed to study the role of statins in preventing
PPDM and other sequelae.
1222 Thiruvengadam et al
Supplementary Material
Note: To access the supplementary material accom-
panying this article, visit the online version of Clinical
Gastroenterology and Hepatology at www.cghjournal.org,
and at http://doi.org/10.1016/j.cgh.2022.05.017.
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diabetes: a collaborative meta-analysis of randomised statin
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rosuvastatin in patients with acute coronary syndrome. Eur
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productSheets/5302_Data_Assets_Chart_Sheet_ISPOR.pdf
Correspondence
Address correspondence to: Nikhil Thiruvengadam, MD, 11234 Anderson
Street, MC 1516, Loma Linda, California 92354. e-mail: nthiruvengadam@llu.
edu; fax: 909-558-2424.
CRediT Authorship Contributions
Nikhil Ravi Thiruvengadam, MD (Conceptualization: Lead; Formal analysis:
Lead; Methodology: Supporting; Writing – original draft: Lead; Writing – review
and editing: Lead)
Douglas Schaubel (Formal analysis: Lead; Methodology: Lead; Supervision:
Lead; Writing – original draft: Supporting; Writing – review and editing: Supporting)
Kimberly A. Forde (Conceptualization: Supporting; Formal analysis: Sup-
porting; Investigation: Supporting; Methodology: Supporting; Writing – original
draft: Supporting; Writing – review and editing: Supporting)
Peter Lee (Conceptualization: Lead; Writing – original draft: Supporting;
Writing – review and editing: Supporting)
Monica Saumoy (Conceptualization: Supporting; Methodology: Supporting;
Writing – original draft: Supporting; Writing – review and editing: Supporting)
Michael L. Kochman (Conceptualization: Lead; Methodology: Supporting;
Supervision: Lead; Writing – original draft: Supporting; Writing – review and
editing: Lead)
Conflicts of interest
The authors disclose no conflicts.
May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e1

Supplementary Index 1. Validation of

Acute Pancreatitis Diagnosis

A total of 75,562 patients had a lipase lab value (using

LOINC code 3040-3) during their index admission in the
Optum database. The mean lipase value was 255  1110 U/
L. A total of 89.57% of these patients’ lipase value was
abnormal with 86.5% being 3 times the upper limit of
normal.

Supplementary Index 2. Details of Statin Therapy Among Regular Statin Users

Supplementary Table 1. Statin Medications Taken Regularly

by Patients With Acute Pancreatitis
From 2007 to 2019

Statin Medication Defined Daily Dose (mg) n (%)

Atorvastatin 20 2908 (32.1)

Simvastatin 30 3204 (35.4)
Rosuvastatin 10 724 (8.0)
Lovastatin 45 878 (9.7)
Pravastatin 30 1050 (11.6)
Pitavastatin 1 224 (2.5)
Fluvastatin 60 60 (0.7)
Total 9048 (100)

Supplementary Table 2. Noncholesterol Medications Taken

Regularly by Patients With Acute
Pancreatitis From 2007 to 2019

Fenofibrate 464 (7.6)

Gemfibrozil 1022 (16.8)

Cholestyramine 860 (14.2)
Colestipol 724 (11.9)
Ezetimibe 1802 (29.7)
Niacin 980 (16.2)
Evolucumab 214 (3.5)
Total 6066 (100)

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1222.e2 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Supplementary Index 3. Distribution of Statin Prescriptions Before and After Acute

Pancreatitis

Supplementary Figure 1. (A) Distribution of statin dispenses for the first dispense before and after the index episode of acute
pancreatitis. The distributions are symmetric (standardized mean difference of 0.04 of months before and after). (B) Distribution
of statin dispenses for the second dispense before and after the index episode of acute pancreatitis. The distributions are
symmetric (standardized mean difference of 0.05 of months before and after). (C) Distribution of statin dispenses for the third
dispense before and after the index episode of acute pancreatitis. The distributions are symmetric (standardized mean dif-
ference of 0.05 of months before and after),

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e3

Supplementary Index 4. Outcome claims for a hemoglobin A1c had a matching laboratory
Validation result listed in Optum.
Diabetes mellitus was defined as a hemoglobin A1c
>6.5%, fasting blood glucose >126 mg/dL, or random
A total of 74,439 patients had laboratory results as
blood glucose >200 mg/dL.1 Using this definition,
part of the Optum Clinformatics dataset. A random
12,559 patients had diabetes prior to the development of
blood glucose was defined using Logical Observation
pancreatitis and were excluded. A total of 10,131 pa-
Identifiers Names and Codes (LOINC) codes 2345-7
tients developed diabetes after the development of
and 2339-0, a fasting blood glucose was defined using
pancreatitis.
the LOINC code 1558-6, and a hemoglobin A1c was
A total of 43,841 patients had no statin exposure
defined using the LOINC codes 4548-4, 4549-2, 17856-
prior to the development of pancreatitis, 3597 were
6, 59261-8, 62388-4, and 4547-6. To assess how
regular statin users, and 14,442 patients were irregular
complete the laboratory data was for these patients we
statin users. Regular statin users had a 64% lower risk of
compared the number of claims with a Current Pro-
developing postpancreatitis diabetes (PPDM) (hazard
cedural Technology code for glycosylated hemoglobin,
ratio [HR], 0.46; 95% confidence interval [CI], 0.40–0.59)
83036 to the number of reported hemoglobin A1c re-
while irregular users had a 46% lower risk of post-
sults in these patients. A total of 88.6% of all submitted
pancreatitis diabetes (HR, 0.64; 95% CI, 0.54–0.72).

Supplementary Index 5. Definition of Comorbidities, Etiology, and Pancreatitis Severity

Supplementary Table 3. ICD definitions for comorbidities utilized in this study

Definition of Covariates Source Code(s)

Hypertension Inpatient Confinement Table or ICD-9: 401–405

Outpatient Physician Medical ICD-10: I10–I15
Claim
Coronary heart disease Inpatient Confinement Table or Myocardial infarction or ischemic heart disease
Outpatient Physician Medical ICD-9: 413
Claim ICD-10: I11, I20–25, I65–66, I70–74
Congestive heart failure Inpatient Confinement Table or ICD-9: 425, 428
Outpatient Physician Medical ICD-10: I11, I130, I42, I43, I50, J81
Claim
Cerebrovascular disease Inpatient Confinement Table or ICD-9: 430–438
Outpatient Physician Medical ICD-10: G45-46, I60–69
Claim
Peripheral vascular disease Inpatient Confinement Table or ICD-9: 443.9
Outpatient Physician Medical ICD-10: I65, I70–77, K55.0–55.1
Claim
Obesity Inpatient Confinement Table or ICD-9: 278, 649B
Outpatient Physician Medical ICD-10: E65.0–67.9
Claim
HIV Inpatient Confinement Table or ICD-9: 042
Outpatient Physician Medical ICD-10: B20.0–22.2; B22.7, B23.0-2, B23.8, B24.9
Claim
Intravenous drug usage Inpatient Confinement Table or ICD-9: 305.90–305.99
Outpatient Physician Medical ICD-10: F19.0–F19.9
Claim

CPT, Current Procedural Technology; ERCP, endoscopic retrograde cholangiopancreatography; PCS, Procedure Coding System.
ICD-9, International Classification of Diseases–Ninth Revision; ICD-10, International Classification of Diseases–Tenth Revision.

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1222.e4 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Supplementary Index 6. Definition of patients had an endoscopic retrograde chol-

Pancreatitis Etiology angiopancreatography with the 7 days prior to the pro-
cedure (including the day of admission). If none of these
were met, patients were classified as having a cause of
In order to identify the etiology of acute pancreatitis
AP of “other.” Etiologies such as drug-induced AP,
(AP), we first determined if patients met the criteria for
autoimmune AP, and hypertriglyceridemia were grouped
alcoholic or gallstone pancreatitis. If there was overlap,
as “other” due to the lack of a validated International
we classified it as a combination. If neither criteria were
Classification of Diseases algorithm to distinguish these
met, we evaluated for postendoscopic retrograde chol-
causes.
angiopancreatography pancreatitis by identifying if

Supplementary Table 4. ICD definitions for etiologies utilized in this study

Alcoholic pancreatitis Inpatient Confinement Table for ICD-9: 577.0 and at least 1 of the
the 577.0 or K85.x and following codes: 291.xx, 303.xx,
Inpatient Confinement Table or 305.xx, 760.71, 980.0, 357.5, 425.5,
Outpatient Physician Medical 535.xx, 571.x ICD-10: K85.XX and at
Claim for the other codes least 1 of the following codes: F10,
E52, G62.1, I42.6, K29.2, K70.x,
T51.x, Z50.2, Z71.4, Z72.1, or
K85.2x
Gallstone pancreatitis Inpatient Confinement Table for ICD-9: 577.0 and at least 1 of the
the 577.0 or K85.x and following: 574.xx, 575.x, 576.x,
Inpatient Confinement Table or 782.4
Outpatient Physician Medical K85.xx and at least 1 of the following:
Claim for the other codes K80 or K81 or K85.1x
Alcoholic/gallstone pancreatitis Inpatient Confinement Table for Patients who have both the codes for
the 577.0 or K85.x and alcoholic pancreatitis and gallstone
Inpatient Confinement Table or pancreatitis
Outpatient Physician Medical
Claim for the other codes
Post-ERCP pancreatitis Inpatient Confinement Table for ICD-9: 577.0 and a procedure code for
the 577.0 or K85.x and ERCP with the 7 d prior to the
Inpatient Confinement admission with AP using (ICD-9-
Table (uses (ICD PCS) or PCS: 51.xx, 52.xx, 97.05 or CPT
Outpatient Procedure Claim 43260-43278)
uses CPT code ICD-9: 85.xx and a procedure code for
ERCP with the 7 days prior to the
admission with AP using (ICD-9-
PCS : 0FJB8ZZ, 0FJD8ZZ,
0F758ZZ, 0F768ZZ, 0F788ZZ,
0F98ZZ, 0F7C8ZZ, 0F9C8ZZ,
0F9580Z, 0F9680Z, 0F9880Z,
0F9980Z, 0F9C80Z, 0F758DZ,
0F768DZ, 0F788DZ, 0F798DZ,
0F7C8DZ, 0F9580Z, 0F9680Z,
0F9880Z, 0F9980Z, 0F9C80Z,
0FC58ZZ, 0FC68ZZ, 0FC88ZZ,
0FC98ZZ, 0FCC8ZZ, 0FF58ZZ,
0FF68ZZ, 0FF88ZZ, 0FF98ZZ,
0FFC8ZZ, 0FJD8ZZ, 0F7D8DZ,
0F7F8DZ, 0F9D80Z, 0F9F80Z,
0FCD8ZZ, 0FCF8ZZ, 0FFD8ZZ,
0FFF8ZZ, 0F7D8ZZ, 0F7F8ZZ, or
CPT 43260-43278)

CPT, Current Procedural Technology; ERCP, endoscopic retrograde cholangiopancreatography; PCS, Procedure Coding System.
ICD-9, International Classification of Diseases–Ninth Revision; ICD-10, International Classification of Diseases–Tenth Revision.

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e5

Supplementary Index 7. Definition of admission or required endoscopic, percutaneous, or

Pancreatitis Severity
The hallmark of the definition of severity in the
revised Atlanta classification is organ failure. Thus we
defined patients as having severe AP if they had organ
failure during their index AP hospitalization or a sub-
sequent AP admission, required intensive care unit (ICU)
surgical intervention for AP.
We defined organ failure using an International
Classification of Diseases–Ninth Revision (ICD-9) algo-
rithm to define organ failure prescribed validated by
Martin et al.2 This was subsequently converted to an
International Classification of Diseases–Tenth Revision
(ICD-10) algorithm.3 ICU admission status was present
in the inpatient confinement table.

Supplementary Table 5. Table summarizing the definitions of organ failure utilized in this study

Respiratory failure Inpatient Confinement Table ICD-9:

518.81—Acute respiratory failure
518.82—Acute respiratory distress syndrome
518.85—Acute respiratory distress syndrome after shock or trauma
786.09—Respiratory insufficiency
799.1—Respiratory arrest
96.7—Ventilator management
ICD-10:
J95.1—Acute pulmonary insufficiency following thoracic surgery
J95.2—Acute pulmonary insufficiency following nonthoracic
surgery
J80—adult respiratory distress syndrome; R06.0, dyspnea
R06.3—periodic breathing
R06.4—hyperventilation
R06.8—other and unspecified abnormalities of breathing
R09.2—respiratory arrest
J96.0—acute respiratory failure
J96.9—respiratory failure, unspecified.
Z99.1—dependence on a ventilator
Cardiovascular failure Inpatient Confinement Table ICD-9 Cardiovascular:
458.0—Hypotension, postural
785.5—Shock
785.51—Shock, cardiogenic
785.59—Shock, circulatory or septic
458.0—Hypotension, postural
458.8—Hypotension, specified type, not elsewhere classified
458.9—Hypotension, arterial, constitutional
796.3—Hypotension, transient
ICD-10:
I95.1—Orthostatic hypotension
I95.8—Hypotension, other
I95.9—Hypotension, unspecified
R03.1—Nonspecific low blood-pressure reading
R57—Shock, not elsewhere classified
R65.2—Septic shock
Renal failure Inpatient Confinement Table ICD-9:
584—Acute renal failure
580—Acute glomerulonephritis
585—Renal shutdown, unspecified
39.95—Hemodialysis
ICD-10:
N00—Acute nephritic syndrome
N01—Rapidly progressive nephritic syndrome
N17—Acute renal failure
N19—Unspecified renal failure
Z49.1—Extracorporeal dialysis

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1222.e6 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Supplementary Table 5. Continued

Hepatic failure Inpatient Confinement Table ICD-9:

570—Acute hepatic failure or necrosis
572.2—Hepatic encephalopathy
573.3—Hepatitis, septic or unspecified
ICD-10:
K72.0—Acute and subacute hepatic failure
K72.9—Hepatic failure, unspecified;
K76.2—Central hemorrhagic necrosis of liver
Hematologic failure Inpatient Confinement Table ICD-9:
286.2—Disseminated intravascular coagulation
286.6—Purpura fulminans
286.9—Coagulopathy
287.3-5—Thrombocytopenia, primary, secondary, or unspecified
ICD-10:
D65—Disseminated intravascular coagulation
D68.9—Coagulation defect, unspecified
D69.3—Idiopathic thrombocytopenic purpura
D69.4—Other primary thrombocytopenia
D69.5—Secondary thrombocytopenia
D69.6—Thrombocytopenia, unspecified
Neurologic failure Inpatient Confinement Table ICD-9:
293—Transient organic psychosis
348.1—Anoxic brain injury
348.3—Encephalopathy, acute
780.01—Coma
780.09—Altered consciousness, unspecified
89.14—Electroencephalography
ICD-10:
F05.0—Delirium not superimposed on dementia
F05.8—Other delirium
F05.9—Delirium, unspecified
G93.1—Anoxic brain damage, not elsewhere classified
G93.4—Encephalopathy, unspecified
R40—Somnolence, stupor and coma
R41.8—Other and unspecified symptoms and signs involving
cognitive functions and awareness
R41.0—Disorientation, unspecified
4A10X4Z—Electroencephalography
Metabolic failure Inpatient Confinement Table ICD-9:
276.2—Acidosis, metabolic or lactic
ICD-10:
E87.2—Acidosis

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e7

Supplementary Index 8. Development of known or putative association with the likelihood of

the Propensity Score Model for Inverse
Probability of Treatment Weighting
To account for potential differences in health status
relevant to the likelihood of receiving a prescription for a
statin, we used multiple propensity score–based
methods. First, we applied inverse probability of treat-
ment weighting (IPTW) such that the weighted statin
and nonstatin populations have the same distribution
with respect to the baseline adjustment covariates; this
makes the adjustment covariates independent of treat-
ment status.
The variables used in the final propensity score
consisted of age, gender, race, education level, income
level, region of the United States, year of index presen-
tation with AP, age-adjusted Charlson comorbidity index,
pancreatitis characteristics (etiology of AP, number of
hospitalization for AP, and length of stay), severity of
pancreatitis (organ failure, ICU admission requirement,
intervention needed for AP, and type of nutritional
support), medical comorbidities, and medications with
receiving a statin prescription.
The medications studied were grouped as antihy-
pertensives group I (diuretics and calcium channel
blockers classified according to the American Hospital
Formulary System Classification codes 402800, 402808,
40280800, 402810, 402812, 40281200, 402816,
40281600, 402820, 40282000, 402824, 40282400,
402892, 40289200, 242800, 242808, 24280800,
242892, or 24289200), antihypertensive group II
(angiotensin-converting enzyme inhibitors and angio-
tensin II receptor blockers 243204, 24320400, 243208,
24320800), anticoagulant treatment (vitamin K antago-
nists, direct thrombin inhibitors, Factor X inhibitors
20120408, 20120412, 20120414, 20120416,
20120492), beta-blockers (242400, 24240000), proton
pump inhibitors (562836, 56283600), Beta-2 agonists
for asthma/chronic obstructive pulmonary disease
(12120812), use of nonaspirin antiplatelet agents
(20121800), and use of antidepressive medications
(281604, 28160412, 28160416, 28160420, 28160424,
28160428, 28160492).

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1222.e8 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Supplementary Index 9. Distribution of minimum propensity score in the regular statin user
the Propensity Score Within Each cohort, we excluded these patients and reassessed the
relationship between regular statin usage and PPDM
Decile, According to Statin Treatment
using IPTW as well as multivariable Cox regression. In
Group After Inverse Probability of this analysis, regular statin usage reduced the rate of
Treatment Weighting PPDM by 43% (HR, 0.57; 95% CI, 0.51–0.64) which
confirmed the results of the primary analysis.
As there was a region of nonoverlap in that 10 statin
nonusers had a propensity score lower than the

Supplementary Figure 2.
Histogram of propensity
scores in the regular statin
user and statin nonuser
cohorts.

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e9
Supplementary Index 10. Supplementary
Analyses
First, we performed propensity-matching using a
nearest-neighbor algorithm to create a matched 1:1
control sample. Second, we evaluated the impact of
pancreatic adenocarcinoma on the relationship between
statin usage and PPDM by stratifying the results by the
development of pancreatic adenocarcinoma. Third, we
then examined the impact of statin usage in patients who
presented with AP after January 1, 2016 (when the ICD-
10 codes were utilized in Optum and the presence of
pancreatic necrosis was defined; in patients with severe
AP (defined as organ failure during their sentinel hos-
pitalization for AP or subsequent hospitalizations, need
for ICU admission, or need for intervention (Supple-
mentary Index 6); and in patients with mild, uncompli-
cated pancreatitis (single admission for AP without
organ failure, ICU admission, or any intervention).
Fourth, to account for potential selection bias, we
included both a negative control exposure and negative
control outcome.4 In such a design, the exposure would
not be expected to have a biological effect on study
outcome but may be influenced by health status or
health-seeking behavior in the same way as the study
exposure (statins in our study). In an unbiased analysis,
there would be no association between the negative
control exposure and the study outcome. For this
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purpose, we used beta-blockers as a possible negative
control exposure given the lack of supporting biological
mechanism or clinical evidence that could explain a
protective effect on PPDM (Supplementary Index 9).5,6
We similarly used a negative control outcome to eval-
uate for unmeasured confounding. We chose low-energy
fractures as the negative control outcome because they
could reflect unhealthy behavior but are unrelated to the
statin effect (Supplementary Index 10).7 We also exam-
ined the impact of regular statin usage in patients who
had an annual preventative visit (which is a surrogate
for positive lifestyle behaviors) in the year prior to their
sentinel episode of AP (Supplementary Index 11).
Pancreatic Cancer
We desired to explore if a diagnosis of pancreatic
cancer was a potential mediator for the relationship
between regular statin usage and the development of
PPDM. A diagnosis of pancreatic cancer required at least
2 outpatient claims >30 days apart or 1 inpatient using
an ICD-9 code of 157.0, 157.1, 157.2, 157.3, 157.8, or
157.9 or an ICD-10 code of C25.1, C25.2, C25.3, C25.7,
C25.8, or C25.9, a previously validated definition.8
Development of pancreatic cancer was included as a
time-varying covariate in the models assessing the
impact of statin usage, and the analysis was stratified by
the development of pancreatic cancer.
1222.e10 Thiruvengadam et al Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5

Supplementary Index 11. 1-to-1
Propensity-Matched Cohort
In one of our sensitivity analyses, we applied an
alternative propensity score–matched cohort design. On
the basis of the propensity score (specified previously)
and index date of hospitalization for AP, each regular
statin user was matched in a 1:1 fixed ratio to a nonuser,
using an established 5 to >2 digit within-caliper greedy
matching algorithm without replacement (using STATA
command psmatch2).14 Using this approach, we suc-
cessfully matched 8171 of the regular statin users to
8171 nonusers to create a propensity score–matched
cohort of 16,342 adults (see Supplementary Table 6
for baseline characteristics).

Supplementary Table 6. Baseline Characteristics of the 1-to-1 Propensity Matched Cohort

Non–Statin Users (n ¼ 8171) Regular Statin Users (n ¼ 8171) P Value

Patient characteristics
Age, y 73 (64–81) 72 (64–80) .01
Male 4137 (50.6) 4059 (49.7) .29
Age-adjusted Charlson comorbidity index 5 (3–8) 5 (3–8) .08
Race .10
White 5696 (69.7) 5782 (70.8)
Black 645 (7.9) 554 (6.8)
Hispanic 736 (9.0) 736 (9.0)
Asian 157 (1.9) 169 (2.1)
Unknown 937 (11.5) 930 (11.4)
Pancreatitis characteristics
Etiology of pancreatitis .46
ETOH/gallstones 1534 (18.8) 1619 (19.8)
ETOH 1146 (14.0) 1154 (14.1)
Gallstones 3561 (43.6) 3484 (42.6)
Post-ERCP 270 (3.3) 281 (3.4)
Other 1660 (20.3) 1633 (20.0)
Number of AP hospitalizations 2 (1–3) 3 (1–4) <.001
Length of stay, d 7 (3–9) 7 (3–10) .52
Severity of pancreatitis
ICU admission 2163 (26.5) 2084 (25.5) .16
SOF during index AP hospitalization 1606 (19.7) 1550 (19.0) .27
MOF during index AP hospitalization 430 (5.3) 399 (4.9) .27
OF by organ system
Pulmonary 533 (6.5) 530 (6.5) .92
Cardiac 222 (2.7) 204 (2.5) .38
Renal 1397 (17.1) 1292 (15.8) .04
Neurologic 179 (2.2) 154 (1.9) .17
Hematologic 114 (1.4) 139 (1.7) .11
Hepatic 81 (1.0) 85 (1.0) .76
Require procedural Intervention for AP 619 (7.6) 669 (8.2) .15
Nutritional support
Enteral nutrition 451 (5.5) 433 (5.3) .53
Parenteral nutrition 256 (3.1) 267 (3.3) .62
Medical comorbidities
Ischemic heart disease 1671 (20.5) 1562 (19.1) .06
Hypertension 7509 (91.9) 7294 (89.3) .01
Obesity 1958 (24.0) 1989 (24.3) .57
Cerebrovascular disease 509 (6.2) 425 (5.2) .01

Values are median (interquartile range) or n (%).

AP, acute pancreatitis; ETOH, alcohol; ERCP, endoscopic retrograde cholangiopancreatography; ICU, intensive care unit; MOF, multiple organ failure; OF, organ
failure; SOF, single organ failure.

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May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e11

Supplementary Index 12. Stratified Models of the Association Between Statin Use and
Risk for PPDM

Supplementary Table 7. Stratified results examining the impact of different covariates on the association between Statin
Usage and PPDM

Multivariable-Adjusted HR (95% CI)

Variable Statin Nonuser Regular Statin User

Age
65 y 1 (ref) 0.86 (0.75–0.98)
>65 y 1 (ref) 0.58 (0.51–0.41)
Sex
1 (ref) 0.56 (0.48–0.70)
Female 1 (ref) 0.57 (0.51–0.64)
Race
Caucasian 1 (ref) 0.65 (0.58–0.72)
Black 1 (ref) 0.61 (0.45–0.83)
Hispanic 1 (ref) 0.51 (0.38–0.68)
Asian 1 (ref) 0.38 (0.19–0.76)
Etiology
ETOH/gallstones 1 (ref) 0.72 (0.61–0.84)
ETOH 1 (ref) 0.60 (0.48–0.73)
Gallstones 1 (ref) 0.70 (0.60–0.83)
Post-ERCP pancreatitis 1 (ref) 0.65 (0.33–1.29)
Other 1 (ref) 0.38 (0.30–0.49)
Charlson comorbidity index
5 1 (ref) 0.56 (0.48–0.64)
>5 1 (ref) 0.50 (0.44–0.56)
SOF during index admission
No 1 (ref) 0.61 (0.56–0.68)
Yes 1 (ref) 0.42 (0.34–0.49)
MOF during index admission
No 1 (ref) 0.58 (0.53–0.63)
Yes 1 (ref) 0.38 (0.24–0.56)
ICU admission
No 1 (ref) 0.66 (0.60–0.73)
Yes 1 (ref) 0.43 (0.37–0.47)
History of ischemic heart disease
No 1 (ref) 0.58 (0.53–0.64)
Yes 1 (ref) 0.55 (0.44–0.69)
History of hypertension
No 1 (ref) 0.56 (0.42–0.73)
Yes 1 (ref) 0.53 (0.48–0.53)
History of obesity
No 1 (ref) 0.59 (0.53–0.65)
Yes 1 (ref) 0.53 (0.44–0.63)
History of cerebrovascular diseases
No 1 (ref) 0.58 (0.53–0.64)
Yes 1 (ref) 0.47 (0.29–0.76)

CI, confidence interval; ETOH, alcohol; ERCP, endoscopic retrograde cholangiopancreatography; HR, hazard ratio; ICU, intensive care unit; IPTW, inverse
probability of treatment weighting; MOF, multiple organ failure; SOF, single organ failure.

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1222.e12 Thiruvengadam et al
Supplementary Index 13. Negative
Control Exposure
Beta-blockers were chosen as the negative control
exposure because they have previously been studied and
they lack of supporting biological mechanism or clinical
evidence that could explain a protective effect on post-
pancreatitis diabetes.5,6 Beta-blocker usage was classi-
fied as the American Hospital Formulary Service code
242400; Patients who had beta-blocker prescriptions
filled for at least 80% of the 1 year preceding their
diagnosis of AP were classified as regular beta-blocker
users.
Of the 118,479 patients, 72,818 patients were beta-
blocker nonusers, 11,186 were beta-blocker regular
users, and 35,075 patients were irregular beta-blocker
users. We used a Cox proportional hazards doubly
robust estimation, in which we combined outcome
regression after propensity score weighting, to estimate
the association between regular beta-blocker usage and
development of PPDM.9
After IPTW was applied, regular beta-blocker usage
was not associated with PPDM (HR, 0.97; 95% CI,
0.90–1.04). This suggests that there are unlikely to be
unmeasured confounders related to healthy user bias or
seeking health care to explain the relationship between
statin usage and PPDM.
Supplementary Index 14. Negative
Control Outcome
Development of atypical hip fracture were chosen as
the negative control outcome because they could reflect
unhealthy behavior, but prior randomized controlled
trials have not shown any effect of statins on their
development.7
We defined low-energy fractures as fractures
possibly due to osteoporosis, typically those caused by
low-energy trauma. The validated ICD-9 criteria for this
group were 805, 807, 808, 811, 812, 813, 820, 821, and
823.10,11 The validated ICD-10 criteria included 28 ICD-
10 codes: M48.4 (vertebral fatigue fracture), M48.5
(vertebral compression fracture, not classified else-
where), M84.3 (stress fracture, not classified elsewhere),
S22.0 (fracture of the thoracic spine), S22.1 (multiple
fractures of the thoracic spine), S22.3 (rib fracture),
S32.0 (fracture of the lumbar spine), S32.1 (fracture of
the sacrum), S32.5 (fracture of the pubis), S32.7 (mul-
tiple fractures of the lumbar spine), S32.8 (other
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Clinical Gastroenterology and Hepatology Vol. 21, Iss. 5
fractures of the lumbar spine), S42.2 (fracture of the
proximal humerus), S42.3 (fracture of the humerus
shaft), S52.2 (fracture of the ulna shaft), S52.5 (fracture
of the distal radius), S52.6 (combined fracture of the
distal radius/ulna), S72.0 (fracture of the femoral neck),
S72.1 (pertrochanteric fracture), S72.2 (subtrochanteric
fracture), S72.4 (fracture of the femur, distal), S72.8
(fracture of the femur, other), S72.9 (fracture of the fe-
mur, no further mention), S82.1 (fracture of the tibia,
proximal), S82.2 (fracture of the tibia shaft), S82.3
(fracture of the tibia, distal), S82.4 (fracture of the fib-
ula), S82.5 (fracture of the malleolar int.), and S82.6
(fracture of the malleolar ext.).12,13
Of the 143,880 patients without a history of low-
energy fractures, 74,780 patients were statin non-
users, 14,605 were statin regular users, and 54,495
patients were irregular statin users. We used a Cox
proportional hazards doubly robust estimation, in
which we combined outcome regression after pro-
pensity score weighting, to estimate the association
between regular statin usage and development of low-
energy fractures.9
After IPTW was applied, regular statin usage was not
associated with PPDM (HR, 0.90; 95% CI, 0.79–1.02).
This suggests that there are unlikely to be unmeasured
confounders that are biasing our results.
Supplementary Index 15. Examination of
Annual Physical Examination as a
Surrogate for Healthy Patient Behavior
We examined annual physical examination visits as a
potential surrogate for healthy user behavior that could
potentially confound the association between regular
statin users and PPDM.
We defined an annual physical examination visit us-
ing the following Current Procedural Technology codes:
99385, 99386, 99387 (Initial preventative visits in
adults); 99395, 99396, 99397 (Follow-up preventative
visits in adults); and G0402, G0438, and G0439 (Medi-
care Annual Wellness visit).
A total of 30,453 (37%) statin nonusers had an
annual physical examination in the year prior to their
sentinel episode of AP compared with 5364 (59%) reg-
ular statin users. When we limited the analysis to pa-
tients who had an annual physical examination visit in
the year prior to their sentinel episode of AP, regular
statin use was associated with a lower risk of PPDM (HR,
0.69; 95% CI, 0.59–0.89).
May 2023 Association of Statin Usage and the Development of Diabetes Mellitus after Acute Pancreatitis 1222.e13

Supplementary Index 16. Sensitivity 0.52–0.65). The E-value for this point was is 2.84 and for
Analysis for Unmeasured Confounding the lower CI limit was 2.4 (Supplementary Figure 3).
Thus, we found that the observed HR of 0.58 could be
explained by an unmeasured confounder that was
Additional sensitivity analysis for the potential effect
associated with both receipt of statin and risk of post-
of unmeasured confounding was performed by the E-
pancreatitis diabetes by a HR of 2.84 each, above and
value methodology of VanderWeele and Ding.15 This
beyond the measured confounders but a weaker
method estimates the minimum strength of association
confounder could not do so.
that would be required between an unmeasured
In our study, it seems implausible to have an un-
confounder and both receipt of a statin and risk of
measured confounder with this large of an association
postpancreatitis diabetes. The calculation is derived
with both the exposure of interest and our outcome
from the HR obtained from an adjusted analysis in
given that is much larger than the observed relationship
observational studies.
for well-known risk factors such as obesity and
For the current study, the HR for postpancreatitis
hypertension.
diabetes with regular statin usage was 0.58 (95% CI,

Supplementary
Figure 3. Curves depicting
the range of joint
confounder associations
for the point estimate.

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1222.e14 Thiruvengadam et al
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