Incretin therapies and risk of hospital admission for acute pancreatitis in an unselected population of European patients with type 2 diabetes: a case-control study

doi:10.1016/S2213-8587(13)70147-5

The Lancet Diabetes & Endocrinology

Volume 2, Issue 2, February 2014, Pages 111-115

https://doi.org/10.1016/S2213-8587(13)70147-5 Get rights and content

Summary

Background

Previous studies have yielded conflicting results about the association between incretin therapies and acute pancreatitis. We aimed to compare the occurrence of acute pancreatitis in a population of patients with type 2 diabetes who received incretins compared with those who received other antidiabetic treatment.

Methods

In our population-based matched case-control study, we extracted information from an administrative database from Piedmont, Italy (containing data for 4·4 million inhabitants). From a dataset of 282 429 patients receiving treatment with antidiabetic drugs for type 2 diabetes, we identified 1003 cases older than 41 years who had been admitted to hospital for acute pancreatitis between Jan 1, 2008, and Dec 31, 2012, and 4012 controls who were matched for sex, age, and time of start of antidiabetic therapy. We compared incretin exposure in cases and controls with a conditional logistic regression model, expressed as odds ratios (ORs [95% CI]). We adjusted all analyses for risk factors of acute pancreatitis, as ascertained by hospital discharge records, and concomitant use of metformin or glibenclamide.

Findings

The mean age of cases and controls (72·2 years [SD 11·1]) was high, as expected in an unselected diabetic population in Europe. After adjustment for available confounders, use of incretins in the 6 months before hospital admission was not associated with increased risk of acute pancreatitis (OR 0·98, 95% CI 0·69–1·38; p=0·8958).

Interpretation

Our findings suggest that, in an unselected population, use of incretins is not associated with an increased risk of acute pancreatitis. Larger studies are needed to clarify whether age or type of incretin therapy could affect the risk of acute pancreatitis in patients with type 2 diabetes.

Funding

Chaira Medica Association, Chieri, Italy.

Introduction

Incretin-based therapies for type 2 diabetes include two drug classes. The first class, glucagon-like peptide-1 (GLP-1) receptor agonists, includes drugs that mimic the action of native GLP-1, such as the injectable GLP-1 analogues exenatide and liraglutide. The other class includes drugs that delay the catabolism of native GLP-1 mainly through inhibition of the endogenous enzyme dipeptidyl peptidase 4 (DPP-4), thus extending the action of native GLP-1. The DPP-4 inhibitors sitagliptin, vildagliptin, saxagliptin, and linagliptin, in order of their prevalence of use in the market in Europe, are all taken orally. Although cases of haemorrhagic or necrotising pancreatitis have been reported in patients taking these drugs, a clear-cut pharmacoepidemiological association between incretin treatment and increased risk of pancreatic damage has not been shown. Incidence of acute pancreatitis is higher in patients with type 2 diabetes than in the non-diabetic population, irrespective of treatment.1, 2 Further complicating the issue is the fact that several drugs commonly used in the treatment of type 2 diabetes (eg, non-incretin anti-diabetes drugs, statins, and angiotensin-converting enzyme inhibitors) have been reported to increase the risk of acute pancreatitis.3, 4, 5

After publication of several studies that were criticised because of inadequate statistical power and short duration of follow-up,6, 7, 8, 9 a report by Singh and colleagues¹⁰ provided some evidence for an association between use of incretins and negative effects on pancreatic function. In their case-control study¹⁰ of an administrative database of adults aged 18–64 years with type 2 diabetes in the USA, treatment with two incretins (sitagliptin and exenatide) was associated with increased chance of hospital admission for acute pancreatitis.

To our knowledge, no such analysis has been done on data from European administrative databases that, owing to the universal nature of most European national health systems, encompass the whole population and include all types of available incretins. Therefore, we aimed to assess whether an association exists between incretin therapies and hospital admissions for acute pancreatitis in unselected European patients with type 2 diabetes.

Section snippets

Study design and participants

In our population-based case-control study, we used regional administrative data from the Piedmont region in northwest Italy, which contains about 4·4 million inhabitants. The population is covered by an automated system of databases that records all drugs dispensed from all regional pharmacies, and hospital discharges reimbursed by the Italian National Health System. These archives can be linked together by a unique anonymous identifier that is encrypted to protect patients' privacy. Because

Results

For the study period examined, 1003 cases of acute pancreatitis and 4012 controls with type 2 diabetes met the inclusion criteria (figure). Compared with controls, prevalence of known risk factors for acute pancreatitis was increased in cases, although other baseline characteristics did not differ (table 1). Prevalence of cardiovascular disease was higher in cases than controls, but prevalence of diabetic retinopathy did not differ between groups. Types of incretin used did not differ between

Discussion

Whether incretin therapies cause acute pancreatitis has raised concern among practitioners.12, 13, 14 In our analysis of a large unselected population of treated individuals with type 2 diabetes, no association was noted between incretin use and incidence of acute pancreatitis, irrespective of causality.

Our findings are in line with previous reports of US administrative databases6, 7, 8, 9 that suggested no link between the use of incretins and pancreatic events in patients with type 2

References (18)

M Elashoff et al.
Pancreatitis, pancreatic, and thyroid cancer with glucagon-like peptide-1-based therapies
Gastroenterology
(2011)
HM Lando et al.
Elevated amylase and lipase levels in patients using glucagon-like peptide-1 receptor agonists or dipeptidyful-peptidase-4 inhibitors in the outpatient setting
Endocr Pract
(2012)
CJ Girman et al.
Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes
Diabetes Obes Metab
(2010)
RA Noel et al.
Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study
Diabetes Care
(2009)
KB Blomgren et al.
Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis
Diabetes Care
(2002)
FL Fimognari et al.
Metformin-induced pancreatitis: a possible adverse drug effect during acute renal failure
Diabetes Care
(2006)
S Mallick
Metformin induced acute pancreatitis precipitated by renal failure
Postgrad Med J
(2004)
R Garg et al.
Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis
Diabetes Care
(2010)
DD Dore et al.
Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide
Curr Med Res Opin
(2009)

There are more references available in the full text version of this article.

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Acute pancreatitis due to different semaglutide regimens: An updated meta-analysis
2024, Endocrinologia, Diabetes y Nutricion
Some concerns persist regarding the safety of semaglutide. The objective of this updated meta-analysis is to assess the risk of acute pancreatitis with the use of semaglutide, assessing the results according to the different administration regimens.
We performed an updated meta-analysis of randomised, placebo-controlled studies of semaglutide therapy that report acute pancreatitis. This meta-analysis was performed in line with PRISMA guidelines. A global and stratified analysis according to the therapeutic scheme used was performed using the fixed-effects model.
Twenty-one eligible trials of semaglutide, including 34,721 patients, were identified and considered eligible for the analyses. Globally, semaglutide therapy was not associated with an increased risk of acute pancreatitis (OR 0.7; 95% CI 0.5–1.2, I² 0%). When we analysed the studies according to the different schemes used, the results were similar (group with oral semaglutide: OR 0.40; 95% CI 0.10–1.60, I² 0%; group with low subcutaneous doses of semaglutide: OR 0.80; 95% CI 0.40–1.90, I² 0%; group with high subcutaneous doses of semaglutide: OR 0.70; 95% CI 0.50–1.20, I² 0%; interaction p-value = 0.689).
This updated meta-analysis demonstrates that the use of semaglutide is not associated with an increased risk of acute pancreatitis compared to placebo. In the stratified analysis, the results were similar with the different semaglutide regimens analysed.
Algunas preocupaciones con respecto a la seguridad de la semaglutida aún persisten. El objetivo del presente metaanálisis actualizado es evaluar el riesgo de pancreatitis aguda con el uso de semaglutida, valorando los resultados según los diferentes esquemas terapéuticos.
Realizamos un metaanálisis actualizado de estudios aleatorizados y controlados con placebo, que hayan evaluado el uso de semaglutida e informaran la incidencia de pancreatitis aguda. Este metaanálisis se llevó a cabo de acuerdo con las directrices PRISMA. Se realizó un análisis global y estratificado según el esquema terapéutico utilizado. Se utilizó un modelo de efectos fijos.
Veintiún ensayos clínicos fueron identificaron y considerados elegibles para este metaanálisis (34.721 pacientes). A nivel global, el tratamiento con semaglutida no se asoció con un mayor riesgo de pancreatitis aguda (OR 0,7; IC 95%: 0,5-1,2; I² 0%). Cuando analizamos los estudios según los diferentes esquemas utilizados, los resultados fueron similares (grupo con semaglutida oral: OR 0,40; IC 95% 0,10-1,60, I² 0%; grupo con dosis subcutáneas bajas de semaglutida: OR 0,80; IC 95% 0,40-1,90, I² 0%; grupo con altas dosis subcutáneas de semaglutida; OR 0,70; IC 95% 0,50-1,20, I² 0%; valor de p de interacción = 0,689).
El presente metaanálisis demostró que el uso de semaglutida no se asoció con un mayor riesgo de pancreatitis aguda en comparación con el placebo. En el análisis estratificado, los resultados fueron similares con los diferentes esquemas de semaglutida analizados.
Incretin-based pharmacotherapy and risk of adverse pancreatic events in the ethnic Chinese with diabetes mellitus: A population-based study in Taiwan
2017, Pancreatology
Citation Excerpt :
We also performed sensitivity analyses to examine whether the main findings met different assumptions for cholelithiasis, alcoholic-related disease, hypertriglyceridemia, and obesity. Our results are in line with previous large cohort studies in the West [2,8,20] and also support recent findings in Asian countries [19]. Compared with previous case-control studies, our population-based cohort study design enables us to establish a Kaplan-Meier curve and to analyze any significant difference between the two cohorts with regard to time to acute pancreatitis.
Pancreatic safety remains a concern for diabetic patients using incretin-based medications. We aimed to determine if there was an association between incretin-based therapy and an increased risk for acute pancreatitis and pancreatic cancer in patients with type 2 diabetes mellitus (DM).
This retrospective population-based cohort study analyzed data from the Taiwan National Health Insurance Research Database. A total of 13 171 eligible type 2 DM patients who had received incretin-based treatment for a minimum of two months were matched 1:1 for age, gender, diabetes complications severity index, and inception date with DM patients who never used this pharmacotherapy. The cohorts were compared for occurrence of acute pancreatitis and pancreatic cancer. The association between incretin-based therapy and acute pancreatitis was assessed using a Cox proportional hazard model and stratified analyses.
Acute pancreatitis occurred in 71 (0.54%) incretin users and 66 (0.50%) non-users, respectively (P = 0.67). The association remained insignificant (adjusted hazard ratio [HR], 1.06; 95% confidence interval [CI] = 0.72–1.55) after adjustment for cholelithiasis (adjusted HR, 2.76; 95% CI = 1.32–5.75) and alcohol-related disease (adjusted HR 9.14, 95% CI = 2.08–40.14) in the Cox model. Stratified analyses affirmed no association between incretin-based therapy and pancreatitis in any subgroup. Pancreatic cancer occurred in 6 (0.05%) and 10 (0.08%) patients in the user and non-user cohort, respectively (P = 0.32).
Incretin-based therapy is not associated with acute pancreatitis and short-term pancreatic cancer risk among ethnic Chinese patients with diabetes. This study supports the pancreatic safety of incretin-based pharmacotherapy.
Sitagliptin use and risk of acute pancreatitis in type 2 diabetes mellitus: A population-based case-control study in Taiwan
2016, European Journal of Internal Medicine
There is still lack of definite evidence to establish the association between sitagliptin use and acute pancreatitis. The study aimed to test this issue in Taiwan.
This case-control study was designed to analyze the database of the Taiwan National Health Insurance Program. There were 349 subjects with type 2 diabetes mellitus aged 20–84 with a first-attack of acute pancreatitis from 2009 to 2011 as the case group and 1116 randomly selected subjects with type 2 diabetes mellitus without acute pancreatitis as the control group. Both groups were matched with sex, age, comorbidities, and index year of diagnosing acute pancreatitis. Current use of sitagliptin was defined as subjects who had their last tablet of sitagliptin ≤ 7 days before the date of diagnosing acute pancreatitis. Late use of sitagliptin was defined as subjects who had their last tablet of sitagliptin between 8 and 30 days before the date of diagnosing acute pancreatitis. Never use of sitagliptin was defined as subjects who never had a sitagliptin prescription. The risk of acute pancreatitis associated with sitagliptin use was estimated by the odds ratio (OR) and 95% confidence interval (CI) using the multivariable logistic regression model.
After statistical correction for potential confounders, the adjusted OR of acute pancreatitis was 2.47 for subjects with current use of sitagliptin (95% CI 0.84, 7.28), when compared with those never using sitagliptin, but without statistical significance. The adjusted OR decreased to 1.14 for subjects with late use of sitagliptin (95% CI 0.66, 1.98), but without statistical significance.
No significant association is detected between sitagliptin use and acute pancreatitis in type 2 diabetes mellitus.
Incretin-based drugs and risk of acute pancreatitis: A nested-case control study within a healthcare database
2015, Diabetes Research and Clinical Practice
Citation Excerpt :
A recent case-control study nested within a large US claim database also reported an almost 2-fold increased risk of acute pancreatitis in users of exenatide and sitagliptin [10]. However, other observational studies based on insurance claim or health databases did not confirm such association [11–17], in agreement with meta- and pooled-analyses of clinical trials (mainly sitagliptin) [18–20]. A recent meta-analysis of randomized and non-randomized studies also suggested that incretin-based drugs do not increase the risk of pancreatitis [21].
To assess the association between use of incretin-based drugs for diabetes mellitus and the occurrence of acute pancreatitis.
A population-based, nested case-control study was performed within a cohort of 166,591 patients from the Lombardy region (Italy) aged 40 years or older who were newly treated with oral antihyperglycaemic agents between 2004 and 2007. Cases were 666 patients who experienced acute pancreatitis from April 1, 2008 until December 31, 2012. For each case patient, up to 20 controls were randomly selected from the cohort and matched on gender, age at cohort entry, and date of index prescription. Conditional logistic regression was used to model the risk of acute pancreatitis associated with use of incretin-based drugs within 30 days before hospitalization, after adjustment for several risk factors, including the use of other antihyperglycaemic agents. Sensitivity analyses were performed in order to account for possible sources of systematic uncertainty.
Use of incretin-based drugs within 30 days was reported by 17 (2.6%) cases of acute pancreatitis versus 193 (1.5%) controls. The corresponding multivariate odds ratio was 1.75 (95% confidence interval, 1.02 to 2.99). Slightly lower and no significant excess risks were observed by shortening (15 days) and increasing (60 and 90 days) the time-window at risk.
This study supports a possible increased risk of acute pancreatitis in relation to use of incretin-baseddrugs reported in a few previous studies. However, given the potential for bias and the inconsistency with other studies, additional investigations are needed to clarify the safety of incretin-based-drugs.
Drug utilization, safety, and effectiveness of exenatide, sitagliptin, and vildagliptin for type 2 diabetes in the real world: Data from the Italian AIFA Anti-diabetics Monitoring Registry
2014, Nutrition, Metabolism and Cardiovascular Diseases
Citation Excerpt :
A 2013 comprehensive review of preclinical and clinical data on pancreatic safety by the European Medicines Agency concluded that the concerns on the risk of pancreatitis should not be minimized [21]. Later, the publication of two large cardiovascular outcome DPP-Is trials [13,22] and epidemiological data [23] stifled the debate; a 2014 joint Food and Drug Administration (FDA)–European Medicines Agency (EMA) assessment concluded with a low-risk [24] but suggested continuous capture of data. As expected, exenatide and DPP4-I add-ons to metformin were accompanied by low rates of hypoglycemia [25].
In Italy, the reimbursed use of incretin mimetics and incretin enhancers was subject to enrollment of patients into a web-based system recording the general demographic and clinical data of patients. We report the utilization data of glucagon-like peptide 1 (GLP1) receptor agonists and dipeptidylpeptidase-4 (DPP4) inhibitors in clinical practice as recorded by the Italian Medicines Agency (AIFA) Monitoring Registry.
From February 2008 to August 2010, 75,283 patients with type 2 diabetes were entered into the registry and treated with exenatide, sitagliptin, or vildagliptin. The treatment was administered to patients in a wide range of ages (≥75 years, n = 6125 cases), body mass index (BMI) (≥35 kg/m², n = 22,015), and metabolic control (HbA_1c ≥ 11% ((96 mmol/mol), n = 3151). Overall, 1116 suspected adverse drug reactions were registered, including 12 cases of acute pancreatitis (six on exenatide). Hypoglycemic episodes mainly occurred in combination with sulfonylureas. Treatment discontinuation for the three drugs (logistic regression analysis) was negatively associated with the male gender and positively with baseline HbA_1c, diabetes duration, and, limitedly to DPP-4 inhibitors, with BMI. Treatment discontinuation (including loss to follow-up, accounting for 21–26%) was frequent. Discontinuation for treatment failure occurred in 7.7% of cases (exenatide), 3.8% (sitagliptin), and 4.1% (vildagliptin), respectively, corresponding to 27–40% of all discontinuations, after excluding lost to follow-up. HbA_1c decreased on average by 0.9–1.0% (9 mmol/mol). Body weight decreased by 3.5% with exenatide and by 1.0–1.5% with DPP-4 inhibitors.
In the real world of Italian diabetes centers, prescriptions of incretins have been made in many cases outside the regulatory limits. Nevertheless, when appropriately utilized, incretins may grant results at least in line with pivotal trials.
Safety of Semaglutide
2021, Frontiers in Endocrinology

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ArticlesIncretin therapies and risk of hospital admission for acute pancreatitis in an unselected population of European patients with type 2 diabetes: a case-control study

Summary

Background

Methods

Findings

Interpretation

Funding

Introduction

Section snippets

Study design and participants

Results

Discussion

Gastroenterology

Endocr Pract

Patients with type 2 diabetes mellitus have higher risk for acute pancreatitis compared with those without diabetes

Diabetes Obes Metab

Increased risk of acute pancreatitis and biliary disease observed in patients with type 2 diabetes: a retrospective cohort study

Diabetes Care

Obesity and treatment of diabetes with glyburide may both be risk factors for acute pancreatitis

Diabetes Care

Metformin-induced pancreatitis: a possible adverse drug effect during acute renal failure

Diabetes Care

Metformin induced acute pancreatitis precipitated by renal failure

Postgrad Med J

Acute pancreatitis in type 2 diabetes treated with exenatide or sitagliptin: a retrospective observational pharmacy claims analysis

Diabetes Care

Use of a claims-based active drug safety surveillance system to assess the risk of acute pancreatitis with exenatide or sitagliptin compared to metformin or glyburide

Curr Med Res Opin

Articles
Incretin therapies and risk of hospital admission for acute pancreatitis in an unselected population of European patients with type 2 diabetes: a case-control study