MD Jean-Luc Faillie

MD MSc Oriana H Yu

MSc Hui Yin

MD Dominique Hillaire-Buys

MD MSc Alan Barkun

PhD Laurent Azoulay
email: laurent.azoulay@mcgill.ca

Association of Bile duct and gallbladder diseases with the use of incretin-based drugs in patients with type 2 diabetes Mellitus

Keywords: Type 2 diabetes, incretin-based drugs, cholelithiasis, cholecystitis, cholangitis, cholecystectomy Population-based cohort study The United Kingdom Clinical Practice Research Datalink linked with the Hospital Episodes Statistics database

Importance: The use of dipeptidylpeptidase-4 (DPP-4) inhibitors and glucagon-like peptide-1 (GLP-1) analogs, a group of drugs used in the management of type 2 diabetes, may be associated with an increased risk of bile duct and gallbladder disease. To date, no observational study has assessed this possible association.

Objective: To determine whether the use of DPP-4 inhibitors and GLP-1 analogs is associated with an increased risk of incident bile duct and gallbladder disease in patients with type 2 diabetes.

Participants: A cohort of 71,369 patients, ≥18 years of age, initiating an antidiabetic drug (including oral and injectable agents) between 2007 and 2014.

Exposure: Current use of DPP-4 inhibitors and GLP-1 analogs (alone or in combination therapy) compared with current use of at least two oral antidiabetic drugs.

Main Outcome and Measures: Time-dependent Cox proportional hazards models were used to estimate hazard ratios (HRs) with 95% confidence intervals (CIs) of incident hospitalized bile duct or gallbladder events (cholelithiasis, cholecystitis, cholangitis), comparing current use of DPP-4 inhibitors and GLP-1 analogs with current use of at least two oral antidiabetic drugs.

Results: During 227,994 person-years of follow-up, 853 patients were hospitalized for bile duct and gallbladder disease (incidence rate [95% CI]: 3.7 [3.5-4.0] per 1000 person-years).

Current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease compared with current use of at least two oral antidiabetic drugs (3.6 vs. 3.3 per 1000 person-years; adjusted HR: 0.99, 95% CI: 0.75-1.32). In contrast, the use of GLP-1 analogs was associated with an increased risk (6.1 vs. 3.3 per 1000 person-years; adjusted HR: 1.79, 95% CI: 1.21-2.67). In a secondary analysis, GLP-1 analogs were also associated with an increased risk of cholecystectomy (adjusted HR: 2.08, 95% CI: 1.08-4.02).

Conclusions and Relevance:

In this population-based study, the use of GLP-1 analogs was associated with an increased risk of bile duct and gallbladder disease. Physicians should be aware of this potential adverse event when prescribing these drugs.

Incretin-based drugs, which include dipeptidyl peptidase-4 (DPP-4) inhibitors and glucagon-like peptide 1 (GLP-1) analogs , are relatively new antidiabetic therapies recommended as second-to third-line treatments in patients with type 2 diabetes. [START_REF] Inzucchi | Management of hyperglycaemia in type 2 diabetes: a patient-centered approach. Position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)[END_REF] DPP-4 inhibitors (such as linaglitin, sitagliptin, vildagliptin and saxagliptin) and GLP-1 analogs (such as exenatide and liraglutide) both induce activation of the GLP-1 receptor, which stimulates insulin secretion in a glucose-dependent fashion, while also inhibiting glucagon secretion. [START_REF] Drucker | Biological actions and therapeutic potential of the glucagon-like peptides[END_REF] In addition to its role in glucose regulation, GLP-1 has also been shown to enhance the proliferation and functional activity of cholangiocytes. [START_REF] Marzioni | Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis[END_REF][START_REF] Marzioni | Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis[END_REF] This raises the concern that the use of incretin-based drugs may increase the risk of bile duct and gallbladder diseases such as cholecystitis and cholangitis, and possibly bile duct cancer. Indeed, according to the World Health Organisation event database, the use of incretin-based drugs has been reported in 1069 cases of bile duct or gallbladder disease (cholelithiasis, cholecystitis, cholangitis) and 79 cases of bile duct or gallbladder malignant neoplasm, worldwilde, since 2007. [START_REF] Vigilyze | Search and analysis tool for VigiBase™ the WHO global ICSR (Individual Case Safety Report) database[END_REF] Furthermore, in a recent randomized controlled trial (RCT), high-dose liraglutide (a GLP-1 analog) for weight loss was associated with an increase in gallbladder-related events (such as cholelithiasis, cholecystitis, and cholecystectomies), compared with placebo. [START_REF] Pi-Sunyer | A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management[END_REF] Although these outcomes are rarely life-threatening or resulting in serious complications, they are painful and often necessitate hospital admissions resulting in costly diagnostic and therapeutic procedures. To our knowledge, no observational study has been conducted to assess this possible association. Such observational studies could provide much needed safety information in the natural setting of clinical practice.

Thus, to address this issue, we conducted a population-based cohort study to determine whether the use of DPP-4 inhibitors and GLP-1 analogs is associated with an increased risk of bile duct and gallbladder disease in patients with type 2 diabetes.

METHODS

Data sources

This study was conducted by linking the United Kingdom (UK) Clinical Practice Research Datalink (CPRD) with the Hospital Episodes Statistics (HES) database. The CPRD records patient-level information from over 13 million patients, representing approximately 8% of the UK population. Patients included in the CPRD have been shown to be representative of the UK population in terms of age and sex. 7 8 The data collected in the CPRD have been shown to be of high quality, [START_REF] Herrett | Validation and validity of diagnoses in the General Practice Research Database: a systematic review[END_REF] and include anthropometric information (such as body mass index [BMI]), lifestyle variables (such as smoking and alcohol use), medical information (such as diagnoses and procedures [coded using the Read code classification]), and prescriptions written by general practitioners (coded according to the UK Prescription Pricing Authority Dictionary).

The HES database contains all inpatient and day case hospital admission information, including primary and secondary diagnoses (coded using the International Classification of Diseases, 10th revision [ICD-10]), and hospital-related procedures. The linkage of the HES database to the CPRD is possible from April 1, 1997 onwards, and is limited to English general practices that have consented to the linkage scheme (currently representing 75% of all English practices). [START_REF] Herrett | Data Resource Profile: Clinical Practice Research Datalink (CPRD)[END_REF] The study protocol was approved by the Independent Scientific Advisory Committee of the CPRD (protocol number 15_235) and by the Research Ethics Board of the Jewish General Hospital, Montreal, Canada.

Study population

We first assembled a base-cohort of patients newly-treated for type 2 diabetes. It consisted of all patients, at least 18 years of age, initiating for the first time a non-insulin antidiabetic drug (metformin, sulfonylureas, prandial glucose regulators, thiazolidinediones, acarbose, DPP-4 inhibitors, and GLP-1 analogs) between April 1, 1998 and December 31, 2013. We excluded patients initially treated with insulin (as these likely represent patients with advanced type 2 diabetes) and women with a history of polycystic ovarian syndrome and gestational diabetes (other known metformin indications). All patients were required to have at least one year of medical history in the CPRD before their first non-insulin prescription.

Using the base-cohort, we assembled a study cohort composed of all patients who initiated a new antidiabetic drug class on or after January 1, 2007 (the year the first incretinbased drug was licensed in the UK). These patients included those newly-treated with a non-insulin antidiabetic drug, as well as those who switched to or added-on an antidiabetic drug from a class not previously used in their treatment history. Cohort entry was defined by the date of this new prescription. We excluded patients previously diagnosed with bile duct and gallbladder diseases (ICD-10 codes listed in eTable 1), primary biliary cirrhosis (ICD-10 code: K74.3) or biliary cancer (ICD-10 codes: C22.1, C23, C24, D37.6, D01.5), human immunodeficiency virus/acquired immunodeficiency syndrome or use of highly-active antiretroviral therapy, [START_REF] Kimura | Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines[END_REF] and haemolytic disorders (such as sickle cell disease or hereditary spherocytosis) [START_REF] Bates | Incidence of gallbladder disease in chronic hemolytic anemia (spherocytosis)[END_REF][START_REF] Bond | Gall stones in sickle cell disease in the United Kingdom[END_REF] at any time before cohort entry (diagnostic codes available upon request). Finally, we also excluded those who used ursodeoxycholic acid/ursodiol and women who were pregnant, in the year before cohort entry.

All patients were followed until an inpatient or day case hospital admission for a bile duct or gallbladder-related condition (cholelithiasis, cholecystitis, cholangitis, gallstone pancreatitis and other bile duct and gallbladder disorders, in primary position; ICD-10 codes listed in eTable 1), or censored upon a pregnancy-related diagnosis, end of registration with the general practice, end of HES-linkability, death from any cause, or end of the study period (March 31, 2014), whichever occured first.

Exposure definition

A time-dependent exposure definition was used in which each person-day of follow-up was classified in one of the following four mutually-exclusive categories: 1) current use of a DPP-4 inhibitor (linagliptin, saxagliptin, sitagliptin or vildagliptin; alone or in combination with other antidiabetic drugs); 2) current use of a GLP-1 analog (exenatide or liraglutide; alone or in combination with other antidiabetic drugs); 3) current use of two or more oral antidiabetic drugs; and 4) other antidiabetic drugs and treatment combinations (which included patients concurrently exposed to DPP-4 inhibitors and GLP-1 analogs [n=1102]). For all categories, exposed person-time was defined by a prescription duration plus a 30-day grace period. Thus, patients were considered continuously exposed if the duration of one prescription overlapped with the date of the next prescription, using the grace period in the event of two non-overlapping successive prescriptions. Since incretin-based drugs are recommended as second-tothird line treatments in the management of type 2 diabetes, [START_REF] Inzucchi | Management of hyperglycemia in type 2 diabetes: a patient-centered approach: position statement of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD)[END_REF] the reference category for all analyses consisted of current use of two or more oral antidiabetic drugs.

Potential confounders

All models were adjusted for the following potential confounders measured at cohort entry: age, sex, year of cohort entry, BMI (<25 kg/m 2 , 25-30 kg/m 2 , ≥30 kg/m 2 ), smoking status (current, past, never), and hemoglobin A1c (HbA1c) level (last measurement before cohort entry). The models were also adjusted for alcohol-related disorders (based on diagnoses related to alcoholism, alcoholic cirrhosis of the liver, alcoholic hepatitis and hepatic failure), diabetic arterial complications (retinopathy, neuropathy, nephropathy, peripheral arteriopathy, myocardial infarction, ischemic stroke), and history of gastric or small intestine bypass surgery; all measured at any time before cohort entry. Finally, we adjusted for the number of physician visits, use of morphinomimetics (which increase pressure of sphincter of Oddi), and fibrates (which inhibit acetyl-coenzyme A acetyltransferase activity); all measured in the year before cohort entry.

Statistical analysis

Cox proportional hazards models using the time-varying exposure definition were used to estimate adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) of hospitalization for bile duct or gallbladder disease associated with current use of GLP-1 analogs and DPP-4 inhibitors, compared with current use of two or more oral antidiabetic drugs. All models were adjusted for potential confounders listed above.

Secondary analyses

We performed three secondary analyses. First, we assessed whether incretin-based drugs were associated with hospitalizations resulting in cholecystectomy. Second, we evaluated whether the risk varied according to duration of continuous use among current users of incretin-based drugs (≤180 days, 180-360 days, and >360 days). Linear trend was assessed by including these duration categories as a continuous variable in the model. Finally, we determined whether duration of treated diabetes modified the association; this was assessed by including an interaction term between duration of treated diabetes (< 5 years vs. ≥ 5 years) and the relevant incretin-based drug exposure categories.

Sensitivity analyses

We conducted six sensitivity analyses to assess the robustness of our findings. First, we repeated the primary analysis using grace periods of 0 and 90 days between successive prescriptions. Second, we repeated the analyses after excluding patients who used insulin (a marker of advanced diabetes) before cohort entry and censoring upon a new prescription during follow-up. Third, we additionally adjusted the analyses for the use of antidiabetic drugs (metformin, sulfonylureas, thiazolidinediones, insulins, and other agents) in the year before cohort entry. Fourth, we repeated the analysis using multiple imputation for variables with missing information, such as BMI, HbA1c, and smoking status. Fifth, we used the disease risk score (DRS) approach as alternate means to control for confounding; [START_REF] Glynn | Role of disease risk scores in comparative effectiveness research with emerging therapies[END_REF] an approach that has been shown to have a comparable performance as the propensity score method (eMethods provides additional information on this method). [START_REF] Arbogast | Performance of disease risk scores, propensity scores, and traditional multivariable outcome regression in the presence of multiple confounders[END_REF] Finally, in order to explore the possibility of ascertainment bias, we performed an analysis excluding and censoring upon pancreatic-related events (acute and chronic pancreatitis, congenital defects of the pancreas and pancreatectomy). All analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC).

RESULTS

The cohort included 71,369 new users of antidiabetic drugs (Figure 1 2). Likewise, the risk did not vary with the duration of use, with all HRs around the null value (Table 2) or when stratifying on duration of treated diabetes (eTable 2). Finally, current use of DPP-4 inhibitors was not associated with a hospitalization resulting in a cholecystectomy (adjusted HR: 1.13, 95% CI: 0.67-1.93).

Table 3 presents the results related to the use of GLP-1 analogs. Compared with current use of two or more oral antidiabetic drugs, current use of GLP-1 analogs was associated with a 79% increased risk of bile duct and gallbladder disease (6.1 vs. 3.3 per 1000 person-years; adjusted HR: 1.79, 95% CI: 1.21-2.67). Duration of treated diabetes did not modify the association (eTable 3). In secondary analyses, the use of GLP-1 analogs for less than 180 days was associated with an increased risk of bile duct and gallbladder disease (HR: 2.01, 95% CI: 1.23-3.29), while longer durations of use were not statistically associated with an increased risk, though these duration categories were based on fewer events (Table 3). Finally, current use of GLP-1 analogs was also associated with an increased risk of undergoing a cholecystectomy (adjusted HR: 2.08, 95% CI: 1.08-4.02).

Sensitivity analyses

The results of the sensitivity analyses are summarized in Figure 2 and presented in the online tables (eTables 2 to 13). Overall, these sensitivity analyses yielded consistent findings, where current use of GLP-1 analogs was consistently associated with an increased risk of bile duct and gallbladder disease, with HRs ranging between 1.59 and 1.84. In contrast, current use of DPP-4 inhibitors was not associated with an increased risk, with HRs ranging between 0.97 and 1.02.

COMMENT

In this population-based cohort study, the use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease. In contrast, the use of GLP-1 analogs was associated with an overall 79% increased risk, which tended to be elevated in the first 180 days of use. Moreover, GLP-1 analogs were also associated with a two-fold increased risk of cholecystectomy. Overall, these findings remained consistent in several sensitivity analyses. Since they necessitated a hospital admission, these outcomes must be considered as serious and, although rare, they might concern a substantial number of patients. Indeed, incretin-based drugs are commonly used in the treatment of type 2 diabetes, and GLP-1 analogs have also been recently approved for obesity management.

To our knowledge, this is the first population-based study investigating the association between incretin-based drugs and the incidence of bile duct and gallbladder disease. Our findings are concordant with the results of a recent large RCT investigating the effects of a high-dose GLP-1 analog (liraglutide) in reducing body weight in overweight and obese patients. [START_REF] Pi-Sunyer | A Randomized, Controlled Trial of 3.0 mg of Liraglutide in Weight Management[END_REF] In this trial, liraglutide use was associated with substantial weight loss, but also an increased risk of gallbladder-related events (such as cholelithiasis and cholecystitis), compared with placebo (61/2481 vs. 12/1242, respectively). The number of cholecystectomies for cholelithiasis and cholecystitis was also imbalanced between the groups (liraglutide: 40/2481 vs. placebo: 6/1242). In a similar trial where the study population comprised overweight patients with type 2 diabetes, the number of patients with gallbladder-related events was also numerically increased in the liraglutide group compared with the placebo group (9/635 and 1/212, respectively). [START_REF] Davies | Efficacy of Liraglutide for Weight Loss Among Patients With Type 2 Diabetes: The SCALE Diabetes Randomized Clinical Trial[END_REF] The rapid weight loss associated with GLP-1 analogs seems to be a logical mechanistic explanation for the increased risk of bile duct and gallbladder diseases. Indeed, weight loss leads to supersaturation of cholesterol in the bile, a known risk factor for gallstones. [START_REF] Erlinger | Gallstones in obesity and weight loss[END_REF][START_REF] Everhart | Contributions of obesity and weight loss to gallstone disease[END_REF] The effect of a rapid weight loss may be related with the fact that we did not find any significant association with longerGLP-1 analog use (over 180 days).

However, in the liraglutide trials, the risk of gallbladder-related events was present across different weight-loss categories, [START_REF]Liraglutide 3.0 mg for Weight Management NDA 206-321[END_REF] suggesting an alternative mechanism. As it was observed in a small cross-over trial of exenatide, [START_REF] Keller | Effect of exenatide on cholecystokinininduced gallbladder emptying in fasting healthy subjects[END_REF] GLP-1 analog use may result in reduced gallbladder emptying. Furthermore, experimental studies indicated that cholangiocytes are susceptible to GLP-1 and respond with increased proliferation and functional activity, which may increase the risk of duct obstruction. [START_REF] Marzioni | Glucagon-like peptide-1 and its receptor agonist exendin-4 modulate cholangiocyte adaptive response to cholestasis[END_REF][START_REF] Marzioni | Exendin-4, a glucagon-like peptide 1 receptor agonist, protects cholangiocytes from apoptosis[END_REF] Therefore, although the weight loss effect of GLP-1 analogs has to be taken into account, it is possible that GLP-1 analogs increase the risk of gallbladder-related events via mechanisms independent of the weight loss effect, or by potentiating its effect.

The fact that the increased risk of bile duct and gallbladder disease was limited to GLP-1 analogs and not DPP-4 inhibitors could be explained by their different effects on GLP-1 pharmacology. Whereas DPP-4 inhibitors increase the half-life of endogenous GLP-1, GLP-1 analogs act as direct exogenous agonists to the GLP-1 receptor, leading to a stronger incretin action. [START_REF] Nauck | Incretin-based therapies for type 2 diabetes mellitus: properties, functions, and clinical implications[END_REF][START_REF] Morales | The pharmacologic basis for clinical differences among GLP-1 receptor agonists and DPP-4 inhibitors[END_REF] This direct mechanism explains the greater incidence of other gastrointestinal side effects (such as nausea and vomiting) and the substantially greater weight loss observed with GLP-1 analogs compared to DPP-4 inhibitors. [START_REF] Drucker | Biological actions and therapeutic potential of the glucagon-like peptides[END_REF][START_REF] Amori | Efficacy and safety of incretin therapy in type 2 diabetes: systematic review and meta-analysis[END_REF][START_REF] Monami | Glucagon-like peptide-1 receptor agonists in type 2 diabetes: a meta-analysis of randomized clinical trials[END_REF] Our study has a number of strengths. First, the use of a large cohort study of patients with type 2 diabetes allowed us to identify a significant number of bile duct or gallbladder events and to corroborate, in a real-world setting, a potential adverse event previously reported in RCTs. Second, the quality of the information recorded in the CPRD is high, and the use of the HES database to identify the outcome likely maximized the validity of the case ascertainment. Finally, the use of a time-dependent exposure definition eliminated immortal time bias. [START_REF] Suissa | Immortal time bias in pharmaco-epidemiology[END_REF] This study has some limitations. Since diabetes severity itself is a known risk factor for bile duct or gallbladder disease, [START_REF] Haffner | Clinical gallbladder disease in NIDDM subjects. Relationship to duration of diabetes and severity of glycemia[END_REF] confounding by indication needs to be considered.

To minimize this potential bias, we compared incretin-based drugs, which are second-to third-line therapies, to current use of two or more oral antidiabetic drugs. Additionally, the models were adjusted for duration of treated diabetes, as well as important potentially confounding factors, including HbA1c and diabetic macro-and microvascular complications as proxies of disease severity. With respect to drug exposures, we had to make the assumption that prescriptions written by general practitioners adequately reflect those of specialists (which are not recorded in the CPRD), and assume appropriate compliance by the patients who were prescribed these drugs. Although such potential misclassifications could have underestimated drug exposure, we do not expect differential renewal or compliance between the exposure groups. With respect to the outcome assessment, GLP-1 analogs are known to be associated with frequent gastrointestinal symptoms (including abdominal pain), and possibly pancreatitis and pancreatic enzyme elevations. Such signs and symptoms may theoretically lead to an over-detection, or perhaps a misdiagnosis, of bile duct and gallbladder disease in GLP-1 analog users. However, while this is possible, we believe that it is unlikely to have affected our findings. First, the most frequently gastrointestinal adverse reaction reported with GLP-1 analogs is mild-to-moderate nausea, a condition that is unlikely to necessitate hospital management. Second, even if patients presented with severe abdominal pain which could be confused with biliary-type pain, a misdiagnosis of bile duct and gallbladder diseases (and a fortiori the ones leading to cholecystectomy) would be highly unlikely given that these conditions are typically confirmed with additional clinical signs and biological test abnormalities, as well as specific imaging findings. Third, our outcome definition was based on an admission diagnosis in primary position (i.e. the diagnosis responsible for the admission), which we believe minimized potential misdiagnoses. Reassuringly, we obtained similar results in a sensitivity analysis that excluded and censored patients with pancreatic-related conditions. Finally, some variables had missing information, such as BMI, HbA1c, and smoking status (ranging between 0% and 18%). However, we obtained nearly identical results in a sensitivity analysis using multiple imputation methods.

In summary, in this large population-based study, we observed an increased risk of bile duct and gallbladder disease with the use of GLP-1 analogs, while no association was observed for DPP-4 inhibitors. Although further studies are needed to confirm our findings and the mechanisms involved, physicians prescribing GLP-1 analogs should be aware of this association, and carefully monitor patients for biliary tract complications.

Table 2

 2 ). The mean (standard deviation [SD]) follow-up time was 3.2 (2.0) years, generating 227,994 personyears of follow-up. Overall, 853 patients had an incident hospital admission for bile duct or gallbladder disease during follow-up, corresponding to an overall incidence rate (95% CI) of 3.7 (3.5-4.0) per 1000 person-years. These admissions included (non-mutually exclusive categories) cholelithiasis (n=563), cholecystitis (n=368), cholangitis (n=5), and other bile duct and gallbladder diseases (n=151). Cholecystectomy was performed in 75 patients (8.8%).Table 1 presents the characteristics of patientswho received DPP-4 inhibitors, GLP-1 analogs, and other antidiabetic drugs at cohort entry. Compared with users of other antidiabetic drugs, users of GLP-1 analogs were younger, more likely to be obese, and to have previously use sulfonylureas or insulin. Overall, both DPP-4 inhibitor and GLP-1 analog users had longer durations of treated diabetes, higher HbA1c levels, and were more likely to have microangiopathic diabetic arterial complications, compared with users of other antidiabetic drugs. The median (first and third quartiles) durations of use for DPP-4 inhibitors and GLP-1 analogs were 365 (156-692) days and 289 (139-538) days, respectively. presents the results related to the use of DPP-4 inhibitors. Compared with current use of two or more oral antidiabetic drugs, current use of DPP-4 inhibitors was not associated with an increased risk of bile duct and gallbladder disease (3.6 vs. 3.3 per 1000 person-years; adjusted HR: 0.99, 95% CI: 0.75-1.32; Table

Figure 1 :Figure 2 :

 12 Figure 1: Study flow chart

Table 1 . Characteristics of users of GLP-1 analog, DPP-4 inhibitors, and other antidiabetic drugs at baseline Exposure groups at baseline

 1

	Characteristics	GLP-1 analogs (n=693)	DPP-4 inhibitors (n=3270)	Other antidiabetic drugs (n=67,406)
	Male, n (%)	409 (59.0)	1932 (59.2)	39,947 (59.3)
	Age (years), mean (SD)	57.2 (10.1)	65.1 (11.3)	62.3 (13.5)
	Body mass index, n (%)
	<25 kg/m 2	S a	325 (9.9)	7630 (11.3)
	25-30 kg/m 2	47 (6.8)	944 (28.9)	20,876 (31)
	≥30 kg/m 2	642 (92.6)	1992 (60.9)	37,240 (55.3)
	Unknown	S a	9 (0.3)	1660 (2.5)
	Smoking, n (%)
	Current	99 (14.3)	420 (12.8)	10,645 (15.8)
	Past	S a	1361 (41.6)	25,405 (37.7)
	Never	304 (43.9)	1489 (45.5)	31,110 (46.2)
	Unknown	S a	0 (0.0)	246 (0.4)
	Alcohol-related disorders, n (%)	37 (5.3)	184 (5.6)	2983 (4.4)
	Hemoglobin A1c, n (%)
	≤7.0 %	85 (12.3)	314 (9.6)	10,375 (15.4)
	7.0%-8.0%	130 (18.8)	1018 (31.1)	17,860 (26.5)
	>8.0 %	473 (68.3)	1905 (58.3)	27,064 (40.2)
	Unknown	5 (0.7)	33 (1.0)	12,107 (18.0)
	Duration of treated diabetes (years), mean (SD) 7.2 (2.9)	7.1 (3.1)	1.0 (2.3)
	Number of physician visits, n (%)	9.5 (9.3)	9.1 (10.1)	7.5 (9.0)
	Diabetic arterial complications, n (%)
	Retinopathy	336 (48.5)	1677 (51.3)	12,241 (18.2)
	Neuropathy	207 (29.9)	898 (27.5)	6906 (10.2)
	Renal disease	140 (20.2)	827 (25.3)	10,439 (15.5)
	Peripheral arteriopathy	34 (4.9)	218 (6.7)	2852 (4.2)
	Myocardial infarction	48 (6.9)	271 (8.3)	5012 (7.4)
	Stroke	20 (2.9)	182 (5.6)	3631 (5.4)
	Gastric or small intestine bypass, n (%)	0 (0.0)	S a	17 (0)
	Morphinomimetics, n (%)	289 (41.7)	1115 (34.1)	19,657 (29.2)
	Fibrates, n (%)	33 (4.8)	92 (2.8)	1087 (1.6)
	Previous antidiabetic drug use, n (%) b
	Metformin	668 (96.4)	3094 (94.6)	62,765 (93.1)
	Sulfonylureas	512 (73.9)	1930 (59.0)	16,850 (25.0)
	Thiazolidinediones	407 (58.7)	1174 (35.9)	5714 (8.5)
	GLP-1 analogs	693 (100.0)	0 (0.0)	0 (0.0)
	DPP-4 inhibitors	0 (0.0)	3270 (100.0)	0 (0.0)
	Insulin	152 (21.9)	146 (4.5)	1938 (2.9)
	Others	52 (7.5)	126 (3.9)	542 (0.8)
	Abbreviations: S, suppressed; SD: standard deviation
	a Cells with less than 5 patients were suppressed, as per the confidentiality policies of the Clinical Practice Research Datalink.

b

Non-mutually exclusive categories; antidiabetic drugs received ever before and including cohort entry

Table 2 . Crude and adjusted HRs for the association between the use of DPP-4 inhibitors and the risk of bile duct disease Current use a Events Person-years Incidence rate (95% CI) b

 2

	Crude HR	Adjusted HR (95% CI) c

Abbreviations: CI, confidence interval; HR, hazard ratio. a Current users of GLP-1 analogs, two or more oral antidiabetic drugs, and other antidiabetic drugs and treatment combinations are not displayed in the table, but were considered in the model for proper estimation of treatment effects. b Per 1000 person-years. c Adjusted for age, sex, calendar year of cohort entry, BMI, smoking status, hemoglobin A1c level, alcohol-related disorders, diabetic arterial complications, history of gastric bypass, number of physician visits in the previous year, and use of morphinomimetics, and fibrates.

Table 3 . Crude and adjusted HRs for the association between the use of GLP-1 analogs and the risk of bile duct and gallbladder disease Current use a Events Person-years Incidence rate (95% CI) b Crude HR Adjusted HR (95% CI) c

 3 Current users of DPP-4 inhibitors, two or more oral antidiabetic drugs, and other antidiabetic drugs and treatment combinations are not displayed in the table, but were considered in the model for proper estimation of treatment effects. Adjusted for age, sex, calendar year of cohort entry, BMI, smoking status, hemoglobin A1c level, alcohol-related disorders, diabetic arterial complications, history of gastric bypass, number of physician visits in the previous year, and use of morphinomimetics, and fibrates.

	Primary analysis
	Two or more oral antidiabetic drugs	170	51,041	3.3 (2.8-3.9)	1.00	1.00 [Reference]
	GLP-1 analogs	30	4916	6.1 (4.1-8.7)	1.87	1.79 (1.21-2.67)
	Duration of GLP-1 analog use
	< 180 days	18	2654	6.8 (4.0-10.7)	2.06	2.01 (1.23-3.29)
	180-360 days	5	995	5.0 (1.6-11.7)	1.52	1.46 (0.60-3.58)
	> 360 days	7	1267	5.5 (2.2-11.4)	1.73	1.61 (0.75-3.46)
						p-trend=0.09

Abbreviations: CI, confidence interval; HR, hazard ratio. a b Per 1000 person-years. c

Study concept and design: Faillie, Yu, Yin, Hillaire-Buys, Barkun, Azoulay.

Acquisition of data: Azoulay.

Analysis and interpretation of data: Faillie, Yu, Yin, Hillaire-Buys, Barkun, Azoulay.

Drafting of the manuscript: Faillie.

Critical revision of the manuscript for important intellectual content: Faillie, Yu, Yin, Hillaire-Buys, Barkun, Azoulay.

Statistical analysis: Faillie, Yin, Azoulay.

Obtained funding: Azoulay.

Study supervision: Azoulay.

Funding/Support: This study was funded by the Canadian Institutes of Health Research.

Role of the sponsor:

The sponsor had no influence on design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, or approval of the manuscript.

Author contributions: Dr. Azoulay had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Conflict of Interest

Details of ethical approval:

The study protocol was approved by the Independent Scientific Advisory Committee of the Clinical Practice Research Datalink (protocol number 15_235) and by the Research Ethics Board of the Jewish General Hospital, Montreal, Canada.

Online-Only Material: Additional information on methods and supplemental tables.